Pharmacological activity, molecular mechanisms and therapeutic potential of erianin (Review)

Introduction

The increasing global cancer burden, with an estimated 20 million new cases and 9.7 million deaths globally in 2022 with projections indicating a 77% increase in incidence by 2050 and the limitations of current treatments, which are exemplified by the fact that despite advancements in cancer detection, treatment and supportive care, survival outcomes remain suboptimal for many patients, together highlight an unmet need for novel therapeutic agents that are both effective and safe (1). There is an unmet need for novel therapeutic agents that are both effective and safe. Plant-derived natural products have attracted attention due to their extensive sources, low toxicity and side effects, high effectiveness and multi-target regulatory characteristics (2). Dendrobium has a long medicinal history and notable pharmacological activity (3).

Erianin is a bibenzyl complex (C18H22O5; Fig. 1) extracted from Dendrobium chrysotoxum (4). This chemical structure endows erianin with a range of pharmacological activities, such as anticancer effects, anti-inflammatory effects, anti-angiogenesis (5). In recent years, studies have revealed that erianin exerts anticancer effects through multi-channel and multi-target mechanisms, including, promoting cancer cell apoptosis and inducing cell cycle arrest (5,6). However, despite its promising biological activity, the clinical development of erianin is hindered by its low water solubility and poor bioavailability, which limits its therapeutic efficacy in vivo. While previous literature has documented the pharmacological effects of erianin (6,7), to the best of our knowledge, there is a lack of comprehensive reviews that bridge the gap between its molecular mechanisms and the pharmaceutical strategies required to overcome its physicochemical limitations.

Figure 1 Chemical structure of erianin. The structure of erianin contains two polyphenol ethers and phenolic hydroxyl benzene rings, which are connected by two saturated carbon atoms. Erianin is a bibenzyl complex isolated from Dendrobium chrysotoxum.

The present review aimed to systematically explain the anticancer basis of erianin through chemical characterization and pharmacological mechanisms, identify the specific limitations regarding its solubility and bioavailability, discuss future applications and delivery strategies to facilitate its development as a clinical drug and provide an example for the drug development of natural products.

Anticancer effects

Respiratory system

Lung cancer (LC)

LC is a type of malignant cancer originating from trachea, bronchial mucosa or glands (8). Previous research has revealed the multi-level mechanism of erianin against LC (9); its core role is derived from its unique biphenyl methyl structure, which enables it to specifically target and regulate the PI3K/Akt/mTOR signaling pathway (10). Notably, erianin induces ferroptosis by activating the Ca2+/calmodulin signaling pathway (11). Therefore, erianin induces both apoptosis and ferroptosis (11).

At the level of metabolic regulation, erianin has shown precise intervention in cancer energy metabolism (12,13). Previous studies have confirmed that erianin has inhibits aerobic glycolysis in non-small cell LC (NSCLC) (2,14), which accounts for 85% of LC (14). Moreover, lung adenocarcinoma (LUAD) is estimated to account for 40% of all lung cancer cases (15). Erianin effectively inhibits the proliferation of cisplatin-resistant cells by regulating the Wnt3/β-catenin signaling pathway (16,17), which provides a novel possibility for overcoming common clinical chemotherapy resistance. In addition, erianin inhibits the proliferation, migration, invasion and angiogenesis of LUAD cells and induces apoptosis by regulating the multiple epidermal growth factor-like domains 9 (MEGF9)/MAPK/ERK signaling pathway (18).

Nasopharyngeal carcinoma

Nasopharyngeal carcinoma is a malignant cancer that originates from the nasopharyngeal mucosal epithelium. Erianin induces caspase cascade-dependent apoptosis, and blocks cell cycle progression by dually activating mitochondrial and death receptor pathways (19). At the same time, erianin inhibits ERK1/2 phosphorylation in a dose-dependent manner and promotes apoptosis by downregulating MMP-9 expression. In conclusion, erianin inhibits nasopharyngeal carcinoma cell proliferation through the ERK1/2-MMP-9 signaling pathway (19). These findings reveal the multi-target anti-nasopharyngeal carcinoma mechanism of erianin and provide options for targeted therapy.

Digestive system

Liver cancer

Hepatocellular carcinoma, the main histological subtype of primary liver cancer, originates from the malignant transformation of liver parenchymal cells or mesenchymal tissue (20). Erianin affects the expression of cancer-associated genes by regulating pyruvate carboxylase (PC)-mediated Wnt/β-catenin signaling pathway, while promoting mitochondrial oxidative stress and inhibiting glycolysis and the proliferation of liver cancer cells (20).

At the molecular level, erianin induces ferroptosis by blocking the JAK2/STAT3/SLC7A11 signaling pathway (21) while regulating the PI3K/Akt and MAPK signaling pathways (22). Erianin can also activate the DNA damage repair pathway by inducing DNA damage, triggering G2/M phase arrest and mitotic cell death, which is complementary to its metabolic regulation (23).

Erianin can simultaneously activate the mitochondrial apoptosis pathway (24) and oxidative stress response (25). Previous experiments in mice have demonstrated tumor growth inhibition without notable toxicity (21). Erianin can also regulate the immune microenvironment, which provides a theoretical basis for its combined application with other treatments, such as chemotherapy, biological immunotherapy, and traditional Chinese medicine (26).

Esophageal cancer (EC)

EC is a highly malignant cancer type originating from the esophageal mucosal epithelium. Erianin can promote MMPs, block cell cycle progression and inhibit MAPK protein activation by dually regulating the JAK/STAT3 and MAPK signaling pathways, thus effectively blocking the proliferation and metastasis of EC cells (27).

In esophageal squamous cell carcinoma (ESCC), erianin exerts an anti-metastasis effect by promoting the ubiquitination and degradation of the outb deubiquitinase 1 (OTUB1) protein (28). Erianin also activates the cyclic guanosine monophosphate/cgmp-dependent protein kinase (cGMP/PKG) signaling pathway, induces apoptosis and inhibits ESCC cell migration (29).

Pancreatic cancer

Pancreatic cancer is a common and highly malignant digestive system cancer derived from pancreatic cells. For example, The American Cancer Society reports that PC is the 10th most common cancer in male and the 8th in female patients in terms of newly diagnosed cases (30). Previous research has shown that erianin significantly inhibits the proliferation and migration and induces the apoptosis of pancreatic cancer cells by dually regulating AKT/FOXO1 and apoptosis signal-regulating kinase 1 (ASK1)/JNK/p38 MAPK signaling pathways (31). Erianin directly interacts with MEK1/2 and blocks the activation of MAPK signaling, thus effectively inhibiting the proliferation of pancreatic cancer cells and the characteristics of cancer stem cells, including suppression of sphere-forming capacity and the downregulation of key stemness markers, such as CD133, CD 44, sex determining region y-box 2 (SOX 2), and octamer-binding transcription factor 4 (OCT 4) (32).

Oral cancer

Oral cancer is a malignant cancer that occurs in the oral cavity. Erianin induces the ferroptosis of oral cancer KB cells and inhibits their proliferation and metastasis by regulating the Nrf2/heme oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4) signaling pathway (33). In oral squamous cell carcinoma, erianin exerts anticancer effects through a dual mechanism: Erianin blocks the cell cycle in the G2/M phase, activates the apoptosis program and regulates autophagy (34) and induces autophagy-dependent apoptosis by inhibiting the palmitoyl-protein thioesterase 1/mTOR signaling pathway (35) and regulating the MAPK pathway (36).

Gastric cancer (GC)

GC is a highly malignant cancer originating from the gastric mucosal epithelium. Erianin significantly inhibits the proliferation, invasion and migration of GC cells by dually regulating the PI3K/AKT and liver kinase b1/salt-inducible kinase 2 or 3/par-3 family cell polarity regulator (LKB1/SIK2/3/PARD3) signaling pathways (37). At the molecular level, erianin not only blocks the activation of the PI3K/AKT pathway, but also effectively reverses the epithelial-mesenchymal transition (EMT) of GC cells by inhibiting LKB1/SIK2/3/PARD3 signal transduction (38).

In addition, a previous study based on network pharmacology confirmed that erianin serves a key role in the treatment of gastric precancerous lesions by regulating the harvey rat sarcoma viral oncogene homolog (HRAS)/PI3K/AKT signaling pathway (39).

Colorectal cancer (CRC)

CRC is a malignant cancer derived from the epithelial cells of the colon and rectum. Erianin significantly induces the apoptosis of CRC cells by dually regulating JNK and MAPK signaling pathways (40) and has a specific anticancer effect on BRAF V600 E or RAS mutant cells (41). In KRAS glycine-to-aspartic acid substitution at codon 13 (G13D) mutant CRC, erianin effectively inhibits cancer cell migration, invasion and EMT by inducing autophagy-dependent ferroptosis (42,43). Erianin induces ferroptosis by promoting GPX4 ubiquitination degradation (44) and upregulating ferredoxin 1 expression (45).

Reproductive system

Breast cancer (BC)

BC is a malignant cancer derived from breast epithelial cells (46). In triple-negative (TN)BC, erianin exerts anticancer effects through a dual mechanism: Erianin activates the mitochondrial apoptosis pathway and inhibits PI3K/Akt signal transduction (46,47) and regulates the cholesterol metabolism pathway by targeting sarcoma gene, which significantly inhibits cancer proliferation and migration (47,48). In estrogen receptor-positive BC, erianin effectively inhibits the proliferation and metastasis of T47D cells by regulating cell cycle progression, inducing apoptosis and balancing MMP/tissue inhibitor of metalloproteinase (TIMP) expression (49).

Erianin shows value in the treatment of bone metastasis of BC. As a novel nuclear factor of activated T cells, cytoplasmic 1 (NFATc1)-specific inhibitor, erianin can effectively block BC-induced pathological osteoclast genesis and decrease bone destruction in MDA-MB-231 breast cancer cell-induced bone loss mice (50).

Cervical cancer

Cervical cancer has the highest incidence of gynecological malignancy, with an incidence rate of 604,127 new cases reported in 2020 (51). Erianin shows a multi-level anticancer mechanism in the treatment of cervical cancer. In terms of immune regulation, erianin serves an important role through dual pathways: Erianin promotes the lysosomal degradation of PD-L1 and blocks the synthesis of hypoxia-inducible factor (HIF)-1α by inhibiting the mTOR/p70 ribosomal protein s6 kinase (S6K)/eukaryotic translation initiation factor 4e-binding protein 1 (4EBP1) pathway (52). Erianin also effectively restores the tumor killing ability of cytotoxic T lymphocytes by inhibiting the MAPK/ERK pathway (52). These immunomodulatory effects have been verified in in vivo experiments, showing anti-proliferative effects.

In terms of apoptosis regulation, erianin shows dose- and time-dependent anticancer properties (53). Erianin regulates the ERK1/2 signaling pathway, which causes HeLa cell cycle arrest in the G2/M phase and activates the mitochondrial apoptotic pathway (53).

Endometrial carcinoma

Endometrial carcinoma is a malignant cancer originating from the endometrial epithelium. Erianin inhibits the proliferation and invasion of endometrial cancer cells by regulating the microRNA (miRNA or miR)-661/bcl-2-related ovarian killer signaling pathway (54).

Prostate cancer

Erianin has unique molecular mechanisms and therapeutic potential in the treatment of prostate cancer (55,56). Erianin increases the levels of C16 ceramide in androgen-sensitive prostate cancer cells, which is associated with the function of ceramide synthase 5 (CerS5) and triggers endoplasmic reticulum stress-associated apoptosis (56).

Nervous system

Glioblastoma (GBM)

GBM is the most aggressive primary cancer of the central nervous system, GBM accounts for 45.6% of all primary brain malignancies. the incidence rate of GBM is 3.19 among 100,000 individuals from different age groups with a median age of 64 years (57). Erianin exhibits a dual cell death induction mechanism in the treatment of GBM (58). Erianin triggers GBM cell apoptosis by inhibiting the Bcl-2 protein and activating the bh3-interacting domain death agonist (Bid) protein (58). Erianin enhances the ferroptosis sensitivity of glioma stem cells and their temozolomide-resistant subsets by promoting the ubiquitination and degradation of the iron transporter SLC40A1 (59). This dual mechanism not only overcomes the drug resistance of the traditional chemotherapeutic drug temozolomide, but also improves the therapeutic effect by simultaneously targeting cancer cells and cancer stem cells. In addition, erianin inhibits EMT by targeting prolyl 4-hydroxylase subunit alpha 1, thereby restoring abnormal tumor blood vessels in GBM, reshaping the immunosuppressive tumor microenvironment and enhancing the efficacy of chimeric antigen receptor (CAR)-T immunotherapy and chemotherapy (60).

Neuroblastoma

Neuroblastoma is a malignant cancer originating from embryonic neural crest cells in the sympathetic nervous system (61). Erianin shows a multi-target anticancer mechanism in the treatment of neuroblastoma (3). Previous research has shown that erianin inhibits the malignant phenotype of SH-SY5Y cells through dual regulation: Erianin promotes the apoptosis of tumor cells by downregulating the expression levels of cancer-promoting Homo sapiens (hsa)-miR-155-5p and hsa-miR-223-3p (62).

Urinary system

Renal cell carcinoma (RCC)

RCC is a highly heterogeneous malignant cancer derived from the renal tubular epithelial system. Erianin could promote N6-methyladenosine modification of arachidonate 12-lipoxygenase, 12s-type/P53 mRNA, regulate ferroptosis-associated signaling pathways and induce ferroptosis in renal cancer cells (63).

Bladder cancer

Bladder cancer is the second most prevalent malignant tumor of the urological system (5.85 cases per 100 000) (64). Erianin shows a multi-target anticancer mechanism in the treatment of bladder cancer (65). Specifically, erianin serves a key role through dual pathways: Erianin effectively induces ferroptosis in bladder cancer cells by inhibiting the NRF2 signaling pathway (65) and, by activating the JNK signaling pathway, triggers cell cycle G2/M phase arrest and promotes apoptosis (66).

Skin system

Melanoma is a common and highly malignant cancer of the skin, it causes 75% of skin cancer-associated mortality due to its high metastatic potential (64). Erianin exerts a significant effect through a dual mechanism: Erianin effectively promotes cancer cell apoptosis and inhibits cell migration by inhibiting the VEGF-α/PI3K/AKT signaling pathway (67) and inhibits the proliferation and survival of BRAF V600E or RAS mutant melanoma cells by simultaneously targeting MEK1/2 and c-raf proto oncogene serine/threonine protein kinase (CRAF) (41).

Blood

Leukemia is a common malignant clonal hematological disease that originates from bone marrow hematopoietic stem cells. Compared with 2020, by 2023, there were 2.4 additional instances per 100,000 people, and the fatality rate had increased to between 1.4 and 1.8 per 100,000 people (68). Erianin serves a significant role through dual pathways: Erianin effectively induces the death of acute myeloid leukemia cells by activating the PPARα signaling pathway and inhibiting PI3K/AKT signal transduction (69) and inhibits the proliferation and promotes the apoptosis of HL-60 leukemia cells by downregulating the expression of the anti-apoptotic protein Bcl-2, upregulating the expression of the pro-apoptotic protein Bax and arresting the cells in the G2/M phase cell cycle (70).

Skeletal system

Osteosarcoma

Osteosarcoma is a common highly malignant bone cancer derived from osteoblasts, accounting for ~35% of all primary bone malignancies. The male-to-female ratio is ~1.5:1.0 (71). Previous in vitro and in vivo experiments have shown that erianin induces cell cycle G2/M phase arrest, apoptosis and autophagy in human osteosarcoma cells by activating the reactive oxygen species (ROS)/JNK signaling pathway and serves an anticancer role (72). Notably, erianin significantly inhibited tumor growth in a xenograft mouse model without notable toxicity (72).

In conclusion, erianin has shown broad-spectrum anticancer activity in a variety of systems and cancer (Fig. 2; Table I). The underlying mechanisms include ferroptosis and anticancer effects by regulating core signaling pathways such as the PI3K/Akt/mTOR, JAK/STAT, MAPK and Wnt/β-catenin pathways (Fig. 3). The anticancer mechanism of erianin has been verified by a multi-disease model, which laid a foundation for clinical transformation. Compared with single highly selective targeted drugs, erianin has wider indications, overcomes cancer heterogeneity, has stronger clinical practicability, inhibits cancer in multiple systems, decreases drug resistance, is suitable for patients with advanced or multiple refractory cancer and has potential as a combination therapy (73).

Figure 2 Mechanism of the broad-spectrum anticancer effect of erianin in human physiological systems. Erianin exerts therapeutic effects not merely through general cytotoxicity, but by modulating distinct signaling networks to trigger apoptosis, ferroptosis and cell cycle arrest across heterogeneous cancer types. (A) In the respiratory system, erianin suppresses lung cancer and nasopharyngeal carcinoma by inhibiting the PI3K/AKT/mTOR pathway and disrupting the ERK1/2/MMP-9 metastatic pathway, alongside inducing CaM-mediated ferroptosis. (B) In the digestive system (liver and esophageal cancers), erianin combats tumors by inducing ferroptosis via the JAK2/STAT3/SLC7A11 pathway and disrupting Wnt/β-catenin signaling, alongside regulating PI3K/Akt and MAPK pathways. (C) In the digestive system (colorectal, gastric, oral, and pancreatic cancers), erianin suppresses malignancies by triggering ferroptosis through GPX4 regulation and the NRF2/HO-1 axis, while inhibiting PI3K/AKT and LKB1/SIK2/3/PARD3 signaling, alongside modulating JNK/MAPK pathways. (D) In the reproductive system, efficacy against breast cancer, cervical cancer, endometrial carcinoma and prostate cancer is driven by immune modulation (PD-L1 degradation), regulation of cholesterol metabolism (SRC signaling) and activation of ceramide-dependent apoptosis. (E) In the nervous system, erianin overcomes glioblastoma and neuroblastoma aggressiveness by inducing a dual cell death mechanism involving miR-mediated apoptosis and SLC40A1-dependent ferroptosis. (F) In the urinary system, therapeutic action in renal cell carcinoma and bladder cancer relies on epigenetic modulation (m6A) and oxidative stress induction via the NRF2 and JNK pathways. (G) In the skin system, erianin combats melanoma by inhibiting the VEGF-α/PI3K/AKT pathway and dual-targeting MEK1/2 and CRAF kinases. (H) In the blood system, erianin fights leukemia by activating PPARα signaling while inhibiting PI3K/AKT, and by downregulating Bcl-2 alongside upregulating Bax to induce apoptosis. (I) In the skeletal system, erianin inhibits osteosarcoma by activating the ROS/JNK signaling pathway, leading to cell cycle arrest, apoptosis, and autophagy. CaM, calmodulin; GPX4, glutathione peroxidase 4; miR, microRNA; m6A, n6-methyladenosine; ROS, reactive oxygen species; MEGF, multiple epidermal growth factor-like domains; PC, pyruvate carboxylase; OTUB, OTU deubiquitinase; cGMP, cyclic guanosine monophosphate; PKG, cGMP-dependent protein kinase; S60K, S6 kinase; 4EBP1, eukaryotic translation initiation factor 4e-binding protein 1; HIF, hypoxia-inducible factor; BOK, bcl-2-related ovarian killer; FDX, ferredoxin; LKB, liver kinase B; SIK, salt-inducible kinase; PARD, partitioning defective; EMT, epithelial-mesenchymal transition; HO, heme oxygenase; PPT, palmitoyl-protein thioesterase; ASK, apoptosis-signal-regulating kinase; P4HA1, prolyl 4-hydroxylase subunit alpha 1; ALOX, arachidonate lipoxygenase; CRAF, C-Raf proto oncogene serine/threonine protein kinase.

Figure 3 Anticancer mechanisms of erianin. Erianin shows versatility and act as a linchpin by regulating shared key signaling pathways. (A) Erianin can target liver and esophageal cancer through the JAK/STAT pathway to induce ferroptosis and block metastasis, downregulating SLC7A11 and disrupting the redox balance. (B) Erianin disrupts fundamental cell survival and proliferation cycles. This triggers caspase-dependent apoptosis and suppresses anti-apoptotic factors in lung, liver, gastric and triple-negative breast cancer as well as leukemia via the PI3K/Akt/mTOR pathway. (C) Erianin can exert multi-target control via the MAPK pathway, modulating JNK, ERK and p38 phosphorylation. This arrests the cell cycle and drives apoptosis in nasopharyngeal, liver, pancreatic, oral squamous cell, colorectal, cervical and bladder cancer, as well as osteosarcoma and melanoma. (D) Erianin can suppress metabolic reprogramming and reverse chemoresistance in liver cancer and lung adenocarcinoma by promoting the degradation of β-catenin and inhibiting its nuclear translocation, thereby regulating the Wnt/β-catenin pathway. ROS, reactive oxygen species; MDA, malondialdehyde; GSH, glutathione; PDK, pyruvate dehydrogenase kinase; PIP, phosphatidylinositol phosphate; BAD, bcl2-associated agonist of cell death; SOS, son of sevenless; MAPKKK, mitogen-activated protein kinase kinase kinase; LRP, low-density lipoprotein receptor-related protein; Dvl, dishevelled; CK, creatine kinase; MARK, microtubule affinity-regulating kinase; APC, adenomatous polyposis coli; GSK, glycogen synthase kinase; CBP, CREB-binding protein; TCF, T cell factor; LEF, lymphoid enhancer-binding factor.

Table I Anticancer effects of erianin.

Table I

Anticancer effects of erianin.

Cancer	Cell	Pathway	Mechanism	(Refs.)
Lung	H1975	PI3K/AKT/mTOR; Ca2+/CaM	Upregulation of Akt, Bax, caspase-3/9, ROS, E-cadherin, CaM, HMOX, Ca2+ and MDA Downregulation of Bcl-2, GSH, GPX4, SLC7A11, N-cadherin, vimentin, Snail, Slug and MMP-9	(10-12)
Non-small cell lung	HCC827	Akt/GSK3β; PI3K/Akt/mTOR	Downregulation of HK2, p-Akt, p-GSK3β and caspase-3	(16)
Lung adenocarcinoma	A549/DDP	Wnt/β-catenin; MEGF9/MAPK/ERK	Upregulation of p-GSK-3β, β-catenin, p-β-catenin, Wnt3, Wnt3a, cyclin D1 and Bcl-2; downregulation of Bax, caspase-3, caspase-9 and survivin	(17,18)
Nasopharyngeal carcinoma	NPC-039 NPC-BM	ERK1/2	Upregulation of BaK, Fas, TNF-R2, DR4/5, RIP, Bim S, caspase-3/8/9, PARP and Bim; downregulation of Bcl-2, p-ERK1/2 and Bcl-xL; decreased ΔΨm	(19)
Liver	HepG2 SMMC-7721; Huh7	JAK2/STAT3/SLC7A11; Wnt/β-catenin; DDR; PI3K/AKT; MAPK	Increased levels of ROS, MDA, Fe2+ and DDR; decreased levels of GSH, SLC7A11, GPX4, PC, p-ERK and p-p38	(21-26)
Esophageal	Eca-109	JAK/STAT3; MAPK	Downregulation of p-STAT-3, p-MAPK, p-JNK, p-p38, p-ERK1 and ERK	(27)
Esophageal squamous cell carcinoma	KYSE-150; KYSE-410; KYSE-450; KYSE-30; KYSE-180; TE-1; TE-10; SHEE	cGMP/PKG	Increased ubiquitin-mediated degradation of OTUB1 protein and cGMP/PKG signaling	(28,29)
Pancreatic	PANC-1; MIA PaCa-2; BxPC-3; SW1990; L3.7	AKT/FOXO1; ASK1/JNK/p38 MAPK	Upregulation of E-cadherin, P21, p-ASK1, p-JNK and p-p38; downregulation of N-cadherin, vimentin, β-catenin, p-Rb, cyclin B1, p-AKT and p-FOXO1	(30-32)
Oral	KB	Nrf2/HO-1/GPX4	Increased levels of ROS, MDA and Fe2+; decreased levels of GSH, GPX4, Nrf2, HO-1 and FTH1	(33)
Oral squamous cell carcinoma	WSU-HN4; SCC-9; CAL-27	PPT1/mTOR; MAPK	Upregulation of caspase-3/8/9, PARP, Bax, Bak, DR5, RIP, LC3-II, p-p38 and p-JNK1/2; downregulation of Bcl-2, Bcl-xL, P62, p-AKT, p-ERK1/2	(34-36)
Gastric	HGC-27	PI3K/AKT; LKB1/SIK2/3/PARD3	Upregulation of LKB1, PARD3, caspase-3, PARP and E-cadherin; downregulation of SIK2/3, N-cadherin, vimentin, Snail and β-catenin	(37-39)
Colorectal	HCT116/LOHP	MAPK; JNK	Downregulation of CRAF, MEK1/2, p-MEK1/2, p-ERK1/2, Bcl-2, Bcl-xL, β-catenin, c-Myc, cyclin D1, CD47 and p-CRAF; upregulation of PARP, Bax and Bak	(40-45)
Breast	MDA-MB-231; MDA-MB-468; EFM-192A	PI3K/AKT; JNK/c-Jun	Upregulation of MUC1, CDK1 and PLAU; downregulation of CCND1, PPARA, PDGFRB, ROCK2, PI3K and p-AKT	(47-50)
Cervical	HeLa; HCT-116; A549; Hep3B; HUVEC	mTOR/p70S6K/4EBP1 MAPK; ERK1/2; HIF-1α/PD-L1	Downregulation of PD-L1, p-ERK1/2 and Bcl-2; upregulation of TFEB, TFE3, MITF, p-AKT, p-GSK3β, p-mTOR, p53 and caspase-3	(52,53)
Endometrial carcinoma	Ishikawa; HEC-251	Not applicable	Upregulation of caspase-3 and Bok; downregulation of Bcl-2	(54)
Prostate	LNCaP; PC3	AR	Upregulation of caspase-3, PARP, IRE1α, p-eIF2α, Bim, LC3-II and C16 ceramide; downregulation of Bcl-2 and p62↓	(55,56)
Glioblastoma	GSCm01R; U87R	Not applicable	Upregulation of VE-cadherin and VEGFR2; downregulation of CD133, SOX2, OCT4, Nanog, Nestin, REST, GPX4, SLC7A11, glutaminase, P4HA1, FSP1, α-SMA, N-cadherin and, P4HA1	(58-60)
Neuroblastoma	SH-SY5Y	Not applicable	mRNA upregulation of caspase-3/7/8 mRNA, FADD, Bid and DR5; downregulation of hsa-miR-155-5p, hsa-miR-223-3p and Bcl-2 mRNA	(62)
Renal cell carcinoma	CD44+/CD105+ HuRCSCs	/	Downregulation of FTH1, GPX4, SLC7A11, IRP2, FTO and p53; upregulation of PTGS2, METTL3/14, WTAP, ALOX12 and global m6A modification	(63)
Bladder	EJ; T24	NRF2; JNK	Upregulation of NRF2, HO-1, xCT, glutaminase, E-cadherin, CAM, Ca2+ and ROS; downregulation of FTH1, GPX4, N-cadherin, vimentin, Slug, Snail, MMP-9 and GSH	(65,66)
Melanoma	C918; MUM-2B uveal melanoma	MAPK; VEGF-α/PI3K/AKT	Downregulation of CRAF, MEK1/2, p-mTOR, p-PI3K, p-AKT, VEGFR2 and VEGF-α	(41,67)
Leukemia	HL-60	MAPK; PI3K/AKT	Upregulation of Bax; downregulation of Bcl-2	(69,70)
Osteosarcoma	143B; MG63.2; Saos2; CCHO	ROS/JNK	Downregulation of cyclin B/D/E1, Bcl-2, Bcl-xl, survivin and p62; upregulation of p21, p27, PARP, caspase-3/8/9, LC3B-II and p-JNK	(72)

[i] ΔΨm, mitochondrial membrane potential; ALOX12, arachidonate 12-lipoxygenase; AR, androgen receptor; ASK1, apoptosis signal-regulating kinase 1; Bak, Bcl-2 homologous antagonist/killer; Bid, Bh3-interacting domain death agonist; Bim, Bcl-2-like protein 11; Bok, Bcl2-related ovarian killer; CaM, calmodulin; CCND1, cyclin D1; CDK1, cyclin-dependent kinase 1; cGMP-PKG, cyclic guanosine monophosphate-protein kinase G; DDR, DNA damage response; DR4/DR5, death receptor 4/5; E-cadherin, epithelial cadherin; eIF2, eukaryotic initiation factor 2; FADD, fas-associated protein with death domain; FSP1, fibroblast-specific protein 1; FTH1, ferritin heavy chain 1; FTO, fat mass and obesity-associated protein; GSC, glioblastoma stem cell; GSH, glutathione; GSK3, glycogen synthase kinase 3; GPX4, glutathione peroxidase 4; HIF-1, hypoxia-inducible factor 1; HK2, hexokinase 2; HMOX1, heme oxygenase 1; HO-1, heme oxygenase 1. HuRCSC, human renal cancer stem cell; IRE1, inositol-requiring enzyme 1; IRP2, iron-responsive element-binding protein 2; LKB1, liver kinase B1; MDA, malondialdehyde; MEK1/2, MAPK/ERK kinase 1/2; MITF, microphthalmia-associated transcription factor; m6A, n6-methyladenosine; MUC1, mucin 1; N-cadherin, neural cadherin; OTUB1, OTU deubiquitinase, ubiquitin aldehyde-binding 1; p70S6K, ribosomal protein S6 kinase β1; PARP, poly (ADP-ribose) polymerase; PARD3, par-3 family cell polarity regulator; P4HA1, prolyl 4-hydroxylase subunit α1; PC, pyruvate carboxylase; PD-L1, programmed death-ligand 1; PLAU, urokinase-type plasminogen activator; PPT1, palmitoyl-protein thioesterase 1; PTGS2, prostaglandin-endoperoxide synthase 2; REST, RE1-silencing transcription factor; RIP, receptor-interacting serine/threonine-protein kinase; ROCK2, rho-associated coiled-coil containing protein kinase 2; ROS, reactive oxygen species; SLC7A11, solute carrier family 7 member 11; TNF-R2, tumor necrosis factor receptor 2; VEGFR2, vascular endothelial growth factor receptor 2; WTAP, Wilms' tumor 1-associated protein; SMA, smooth muscle action.

The broad-spectrum anticancer biological activity of erianin is based on the precise regulation of key signaling networks (Fig. 3). Erianin induces specific cell death modalities such as ferroptosis via the JAK/STAT pathway and reverses chemotherapy resistance (21) and reprograms metabolism through the Wnt/β-catenin pathway (16). These converging mechanisms constitute the molecular basis for the universality and therapeutic potential of erianin against heterogeneous types of malignancy.

However, erianin may possess drug toxicity, and needs to balance efficacy and safety. A previous study found that erianin is stable, has low toxicity and shows consistent sensitivity and reliability in rat plasma under specific storage conditions (including long-term storage at low temperatures, short-term stability at room temperature and freeze-thaw cycle stability) (74), which provides a practical basis for clinical application.

Other effects

Complications of diabetes

Diabetes mellitus is a chronic metabolic disease characterized by persistent hyperglycemia (71). Erianin exerts multi-target regulation in the prevention and treatment of diabetic microvascular complications. Previous research has shown that erianin serves a protective role in diabetic retinopathy (DR) and diabetic nephropathy (DN) by co-targeting the NF-κB inflammatory pathway (75,76). In DR, erianin attenuates microglia-mediated retinal inflammation by inhibiting the ERK1/2-NF-κB signaling pathway (75), while blocking TNF-α-induced blood-retinal barrier damage (77).

In DN, erianin effectively protects renal tubular epithelial cells from high glucose injury by regulating the ROS/MAPK/NF-κB signaling pathway (76). These findings not only reveal the molecular basis of erianin in the prevention and treatment of diabetic microvascular complications through the dual mechanisms of anti-inflammation and anti-oxidative stress, but also provide a theoretical basis for the development of treatment strategies for diabetic complications based on natural products.

Diabetes is the leading cause of cardiovascular disease worldwide. Diabetic cardiomyopathy (DCM) is a complication with limited treatment options, as effective strategies remain elusive and glycemic control is still the primary approach (77,78). The hyperglycemic state in DCM disrupts cardiac energy metabolism and induces mitochondrial dysfunction, which represents a key pathological feature that is also implicated in other cardiac injuries such as myocardial ischemia-reperfusion injury (79). Erianin can effectively reduce myocardial injury, improve cardiac function and inhibit myocardial remodeling in a mouse model of type 2 diabetes by activating the AMPK/Nrf2/HO-1 signaling pathway (80). These findings not only reveal the cardioprotective effect of erianin through the dual mechanisms of antioxidant stress pathway (Nrf2/HO-1 mediated) and energy metabolism regulation (AMPK-dependent), but also provide a theoretical basis for the development of natural product-based DCM treatment strategies.

However, despite preclinical studies (5,8,11), erianin faces important challenges in practical applications. The optimal therapeutic dose and long-term safety of erianin are not clear, and there is a lack of large-scale clinical trial verification. Future research needs to focus on pharmacodynamic optimization and clinical transformation to realize the potential value of erianin in the treatment of diabetic complications.

Anti-angiogenesis

Erianin exhibits a multi-level inhibitory effect in the regulation of angiogenesis. In retinopathy, erianin inhibits inflammation-related angiogenesis by blocking the ERK1/2-NF-κB and HIF-1α/VEGF/VEGFR2 signaling pathways (81). By interfering with the collagen-integrin interaction, RhoA/ROCK1 signaling is inhibited to block collagen-mediated angiogenesis (82).

In the regulation of cancer angiogenesis, erianin exhibits multi-target characteristics, including inhibiting endothelial cell metabolism via the JNK/stress-activated protein kinase-dependent pathway and disrupting the cytoskeleton (F-actin and β-tubulin) to affect endothelial cell migration (83). In addition, erianin inhibits the proliferation of human umbilical vein endothelial cells and formation of vascular endothelium and weakens the adhesion to fibronectin and cross-collagen migration, thus inhibiting cancer angiogenesis (84). Furthermore, erianin protects endothelial cells from oxidative damage via the Nrf2 pathway (85) and downregulates the JAK2/STAT3 signaling pathway and its downstream effectors (86). The key features of the anti-angiogenic effects of erianin include targeting the key signaling pathways of angiogenesis and regulating the basic biological processes of endothelial cells, as well as both anti-inflammatory and antioxidant effects. This makes erianin a potential candidate for the treatment of angiogenesis-related diseases, and provides an important theoretical basis for the development of novel anti-angiogenesis strategies. However, its selective regulation mechanism of angiogenesis in different tissue remains to be further elucidated.

Anti-inflammation

Chronic inflammation

Erianin has shown extensive therapeutic potential in chronic inflammation-related diseases, such as ulcerative colitis, rheumatoid arthritis, osteoarthritis, chronic atrophic gastritis and psoriasis (87-94,95,96). Previous studies have shown that erianin exhibits anti-inflammatory activity by directly inhibiting the assembly and activation of NLRP3 inflammasomes (87,95). In ulcerative colitis, erianin serves a role through a dual mechanism: On the one hand, erianin reduces the expression of the pro-inflammation factors IL-6 and IL-8 by inhibiting the TLR4/TRAF6/NF-κB signaling pathway. On the other hand, erianin restores immune homeostasis by regulating the IL-2 levels (88). Similarly, erianin also has potential in the treatment of rheumatoid arthritis, where it inhibits the abnormal activation and polarization of T helper 17 cells by targeting the JAK/STAT3 signaling pathway (89). In addition, erianin serves a protective role in osteoarthritis by activating the GPX4/STING signaling pathway and inhibiting IL-1β-induced chondrocyte ferroptosis, oxidative stress and extracellular matrix degradation (90).

In chronic atrophic gastritis, erianin exhibits a regulatory role in maintaining autophagy homeostasis by balancing the activity of the MAPK/mTOR signaling pathway (91). The key core mechanisms of the anti-inflammatory effects of erianin include direct targeting of inflammasomes, regulation of key inflammation signaling pathways and maintenance of immune cell balance.

Psoriasis is a chronic recurrent inflammation skin disease characterized by excessive proliferation and abnormal differentiation of keratinocytes, resulting in impaired epidermal barrier function. Previous mechanistic studies have shown that erianin activates the JNK/c-Jun pathway in a ROS-dependent manner and inhibits AKT/mTOR signaling, thereby regulating the proliferation and differentiation of keratinocytes (92,96). These findings not only reveal the mechanism of erianin in the treatment of psoriasis, but also provide an experimental basis for the development of psoriasis treatment strategies based on ROS signal regulation.

Alopecia areata (AA) is a sudden-onset non-scarring hair disease (93). Erianin regulates the IFN-γ signaling pathway and inhibits cell populations closely related to the pathogenesis of AA (94). It is necessary to explore the causes and pathophysiological mechanisms of AA for the development of more effective treatment methods.

Acute inflammation

Myocarditis is a type of myocardial inflammation disease that leads to severe arrhythmia. It is the primary cause of dilated cardiomyopathy and may lead to heart failure (97). Erianin has shown notable anti-inflammatory activity and organ protection in acute inflammatory diseases, such as myocarditis and acute lung injury (98-100). In myocardial inflammation, erianin exerts therapeutic effects through a dual mechanism: Inhibiting the NF-κB and NLRP3 signaling pathways, decreasing M1 macrophage polarization and improving myocardial fibrosis and dysfunction to alleviate autoimmune myocarditis (98). By activating the Keap1/Nrf2 antioxidant pathway, reducing anthracycline-induced cardiotoxicity such as doxorubicin (DOX) and improving cardiac systolic function, erianin provides dual protection against chemotherapy-associated heart damage (99).

The lung is susceptible to acute inflammation and subsequent injury due to its extensive microvascular network and direct exposure to external stimuli. P-selectin is a potential therapeutic target for acute inflammation (100). Erianin mitigates lipopolysaccharide-induced acute lung injury in mice, reducing total cells, neutrophils and protein content in bronchoalveolar lavage fluid (BALF), as well as suppressing pro-inflammatory cytokines in both lung tissue and BALF (100).

In vivo, erianin inhibits NF-κB pathway activation in lung tissue, but does not attenuate inflammation responses in human pulmonary microvascular endothelial cells (HPMECs) in vitro (99). Mechanistically, erianin blocks neutrophil adhesion and transient adhesion-mediated movement along the surface of HPMECs by decreasing the binding affinity between P-selectin and p-selectin glycoprotein ligand-1 without altering P-selectin expression or membrane translocation (101).

This multi-target action characteristic makes erianin a potential candidate for the treatment of inflammation-associated diseases, and provides a theoretical basis for the development of new anti-inflammatory strategies.

Anti-virus

Human enterovirus 68 (EVD68) is an emerging viral pathogen that has received increasing attention due to its association with severe respiratory disease, such as asthma exacerbations, community-acquired pneumonia and typical acute respiratory illness (102-104). Erianin inhibits the production of EVD68 by inducing G2/M blockade (105), thus suggesting the potential application of erianin in antiviral research.

Anti-oxidation

Oxygen free radicals and lipid peroxides are associated with the etiology of aging and diseases such as cancer, multiple sclerosis, Parkinson's disease, senile dementia, autoimmune disease and asbestosis (106). Erianin can effectively inhibit the abnormal activation of the ERK1/c-Jun signaling pathway following traumatic brain injury (TBI), and reduce oxidative stress and inflammation response in brain tissue (107). This reveals the antioxidant mechanism of erianin in TBI treatment.

Anti-drug resistance

Erianin exhibits a dual mechanism of action in overcoming cancer multidrug resistance (MDR). In an oxaliplatin-resistant model of colon cancer, erianin downregulates the expression of drug efflux protein P-glycoprotein (P-gp) by specifically inhibiting the JAK2/STAT3 signaling pathway, thereby effectively reversing the MDR phenotype of cancer cells (108). Erianin can also directly target the colchicine binding site of β-tubulin and impair the integrity of the cytoskeleton by inhibiting microtubule polymerization (109). This mechanism not only overcomes paclitaxel resistance (109), but also explains broad-spectrum anticancer activity of erianin.

Key mechanisms of erianin in overcoming cancer drug resistance include the regulation of drug transport systems and targeting of key components of the cytoskeleton, as well as the regulation of signaling pathways and direct cytotoxicity (108,109). This makes erianin a potential candidate drug to overcome cancer drug resistance, which provides a molecular mechanism basis and theoretical support for the development of novel MDR reversal strategies (109). Selective regulation mechanism of erianin on the resistance of different types of chemotherapeutic drug remains to be further elucidated.

Anti-bacteria

Staphylococcus aureus is a Gram-positive opportunistic pathogen. Sortase A (SrtA) is a key transpeptidase of Gram-positive bacteria. Erianin blocks the entry and binding of T-G peptide chain and lipid II of surface protein to the SrtA biological active center and effectively inhibits the anchoring function of transpeptidase (110). This finding reveals the mechanism of erianin against S. aureus infection and provides important theoretical basis and potential therapeutic targets for the development of novel anti-infection strategies based on SrtA inhibition.

Loss of neuronal protection

Erianin has shown neuroprotective effects in neurological diseases such as traumatic brain injury, cerebral ischemia-reperfusion injury and Parkinson's disease (105,111-113), and its mechanism of action primarily involves the regulation of key signaling pathways. In acute BI, erianin exerts a protective effect through a dual mechanism: In cerebral ischemia-reperfusion injury, erianin inhibits microglia-mediated neuroinflammation by regulating the PI3K/AKT and NF-κB pathways (111). In TBI, erianin attenuates neuronal injury by inhibiting the ERK1/c-Jun signaling pathway (105).

Erianin significantly alleviates neuroinflammation in a Parkinson's disease model by inhibiting the NF-κB/NLRP3 inflammasome pathway (112). Erianin promotes neuronal differentiation by regulating ERK1/c-Jun signaling (113). The aforementioned studies have revealed that the key mechanisms of neuroprotection of erianin include regulating the inflammatory response (NF-κB/NLRP3 pathway), maintaining neuronal survival (PI3K/AKT pathway) and promoting nerve regeneration (ERK1/c-Jun pathway). This makes erianin a potential candidate drug for the treatment of neurological disease and provides an important theoretical basis for the development of neuroprotection strategies based on signaling pathway regulation.

Anti-hepatic steatosis

Decreased vascular endothelial (VE)-cadherin expression in hepatic vascular endothelial cells is associated with hepatic steatosis in the early stage of non-alcoholic fatty liver disease (NAFLD); erianin could reduce hepatic steatosis by enhancing Nrf2-mediated VE-cadherin expression (114).

In conclusion, a number of studies have confirmed that erianin exhibits pharmacological activity beyond its antitumor activity (5,6). Erianin functions as a pleiotropic agent capable of restoring homeostasis across diverse pathological microenvironments (Fig. 4; Table II). Erianin is used in a treatments, ranging from reducing diabetic complications and inhibiting pathological angiogenesis, to alleviating acute and chronic inflammation, as well as for other biological activities, including neuroprotection, anti-hepatic steatosis, anti-microbial effects (antiviral and antibacterial), anti-oxidation and reversal of drug resistance. These bioactivities are driven by the ability of erianin to modulate key signaling pathways, primarily the inflammatory NF-κB/NLRP3 pathway, the oxidative stress-responsive Nrf2 pathway and cytoskeletal dynamics. By simultaneously targeting upstream receptors and downstream effectors, erianin serves as a multi-target candidate for complex disease management. However, the poor water solubility and low bioavailability of erianin limit its practical applications (6). In recent years, researchers have effectively improved the water solubility and bioavailability of erianin by chemical modification, new manufacturing technology and structural optimization (Fig. 5; Table III) (5).

Figure 4 Multi-system therapeutic potential of erianin, Erianin mitigates diabetic complications, including diabetic retinopathy, nephropathy and cardiomyopathy by decreasing oxidative stress and inflammation. Erianin serves a role in inhibiting retinal and cancer angiogenesis. Erianin reverses chronic inflammation (such as ulcerative colitis, rheumatoid arthritis, osteoarthritis and chronic atrophic gastritis) and acute inflammation (such as myocarditis and pneumonia). Erianin exhibits anti-viral, antioxidant, anti-drug resistance, anti-bacterial, anti-psoriasis, anti-alopecia, neuroprotective and anti-hepatic steatosis effects.

Figure 5 Strategic structural modifications of erianin. Derivatives are focused on enhancing bioavailability and multi-target effects to overcome drug resistance. Ecust 004 (sulfamate) serves as a dual tubulin/steroid sulfatase inhibitor to reverse epithelial-mesenchymal transition. Phosphorylated EBTP targets the PI3K/Akt pathway for anti-angiogenesis. HDAC1/6 inhibitors (27f and 39f) as well as ZJU-6 offer multi-target regulation of epigenetics and angiogenesis. Analogues are focused on metabolic targeting and theranostics. ZY-444 inhibits the metabolic enzyme pyruvate carboxylase in breast cancer, while [18F]FEE facilitates PET imaging of hepatocellular carcinoma. Erianin-ruthenium (II) conjugates serve as G4 DNA stabilizers, suppressing c-myc oncogene expression through specific metal coordination. EBTP, 2-Ethoxy-5-(3,4,5-trimethoxyphenethyl)phenol phosphate disodium salt; HDAC, histone deacetylase.

Table II Non-anticancer effects of erianin.

Table II

Non-anticancer effects of erianin.

A, Diabetic complications
Disease	Pathway	Mechanism	(Refs.)
Diabetic retinopathy	ERK1/2-NF-κB	Upregulation of occludin and claudin-1; downregulation of Iba1, NLRP3, ASC, caspase-1, p-IKK, p-IκB, p-p65, p-ERK1/2, GLUT1, p-c-Raf and p-MEK1/2	(75,77)
Diabetic nephropathy	JNK; MAPK; ROS/MAPK/NF-κB	Upregulation of caspase-3/9, Bax, ROS and MDA; downregulation of Bcl-2 and GSH	(76)
Diabetic cardiomyopathy	AMPK/Nrf2/HO-1	Downregulation of p-AMPKα, Nrf2, HO-1 and NQO1	(77,79)
B, Anti-angiogenesis
Anti-retinal angiogenesis	ERK 1/2-NF-κB; HIF-1α/VEGF/VEGFR2; RhoA/ROCK1	Downregulation of integrin α2/β1, GTP-RhoA, ROCK1 and p-MYPT1	(81,82)
Anti-cancer angiogenesis	JNK/SAPK; JAK2/STAT3; Nrf2	Downregulation of p-STAT3, p-JAK2, MMP-2/9, HIF-1α, COX-2 and IL-6	(83-86)
C, Anti-inflammation
Ulcerative colitis	JAK2/STAT3; NF-κB	Upregulation of TLR4, TRAF6, p-IKKα/β, p-IκBα, p-NF-κB p65, NF-κB p65, p-JAK2, p-STAT3 and p-Akt; downregulation of IκBα	(88)
Rheumatoid arthritis	JAK/STAT3	Downregulation of p-JAK2 and p-STAT3	(89)
Osteoarthritis	GPX4/STING	Upregulation of IL-1β, MMP-13, ADAMTS-5, iNOS, COX2, IL-6, TNF-α, p-TBK1 and p-IRF3; downregulation of p-GPX4, collagen II, aggrecan and STING	(90)
Chronic atrophic gastritis	MAPK/mTOR	Upregulation of P62/SQSTM1, LC3-II, Beclin1, p-p38 MAPK and p-mTOR	(91)
Psoriasis	JNK/c-Jun; Akt/mTOR	Upregulation of ROS, caspase-3, PARP, p-JNK, p-c-Jun and c-Jun; downregulation of p-AKT and p-mTOR	(92,96)
Alopecia areata	IFN-γ	Downregulation of MHC-I/II, GZMB+, PD-1+ and IFN-γ/IL-2	(94)
Myocarditis	NF-κB/NLRP3; Keap/Nrf2	Upregulation of Nrf2, HO-1, Bax, LC3B-II and SOD2; downregulation of Keap1, Bcl-2, P62 and P67	(97-99)
Acute lung injury	NF-κB	Upregulation of IκBα; downregulation of p-IκBα, p-p65, TNF-α, IL-6, IL-1β and PSGL-1/P-selectin binding	(100,101)
D, Anti-virus
Human enterovirus 68	Not applicable	Downregulation of VP1, cyclin B1 and CDK1	(105)
E, Anti-oxidation
Traumatic brain injury	ERK1/c-Jun	Upregulation of p-ERK1, p-c-Jun and c-Jun; downregulation of DCX	(107)
F, Anti-drug resistance
Disease	Pathway	Mechanism	(Refs.)
Oxaliplatin resistance	JAK2/STAT3	Upregulation of Bax; downregulation of Bcl-2, c-Myc, cyclin D1, HIF-1α, P-gp, p-JAK2 and p-STAT3	(108-109)
G, Anti-bacterial
Staphylococcus aureus	/	Downregulation of SrtA	(110)
H, Loss of neuronal protection
Traumatic brain injury	ERK1/c-Jun	Downregulation of MHC-I/II, GZMB+, PD-1+ and IFN-γ/IL-2	(105)
Cerebral ischemia-reperfusion injury	PI3K/AKT; NF-κB	Upregulation of Bax, caspase-3, CD86, CD32, COX-2, TNF-α, IL-6 and p-P65; downregulation of Bcl-2	(111)
Parkinson disease	NF-κB/NLRP3	Upregulation of GFAP, Iba-1, NLRP3, ASC, caspase-1, IL-1β, IL-18, NEK7 and p-NF-κB p65; downregulation of TH↓	(112)
I, Anti-hepatic steatosis
Hepatic steatosis	Nrf2	Upregulation of VE-cadherin and N-Nrf2; downregulation of N-GATA4	(114)

[i] ADAMTS-5, a disintegrin and metalloproteinase with thrombospondin motifs 5; AMPK, AMP-activated protein kinase; ASC, apoptosis-associated speck-like protein containing a CARD; CDK1, cyclin-dependent kinase 1; COX-2, cyclooxygenase-2; DCX, doublecortin; GATA4, GATA-binding protein 4; GFAP, glial fibrillary acidic protein; GLUT1, glucose transporter 1; GSH, glutathione; GZMB, granzyme B; HIF-1, hypoxia-inducible factor 1; HO-1, heme oxygenase 1; Iba-1, ionized calcium-binding adapter molecule 1; iNOS, inducible nitric oxide synthase; IKK, IκB kinase; LC3, microtubule-associated proteins 1A/1B light chain 3B; MDA, malondialdehyde; MEK, MAPK/ERK kinase; MHC-I, major histocompatibility complex class I; MYPT1, myosin phosphatase target subunit 1; NEK7, NIMA-related kinase 7; NLRP3, NOD-like receptor pyrin domain containing 3; NQO1, NAD(P)H quinone dehydrogenase 1; p-, phosphorylated; PARP, poly (ADP-ribose) polymerase; PD-1, programmed cell death protein 1; PI3K, phosphoinositide 3-kinase; P-gp, p-glycoprotein; TBK1, TANK-binding kinase 1; IRF3, interferon regulatory factor 3; GPX4, glutathione peroxidase 4; PSGL-1, p-selectin glycoprotein ligand-1; ROCK1, rho-associated coiled-coil containing protein kinase 1; ROS, reactive oxygen species; SAPK, stress-activated protein kinase; SOD2, superoxide dismutase 2; SQSTM1/p62, sequestosome 1; SrtA, sortase A; STING, stimulator of interferon genes; TH, tyrosine hydroxylase; TLR4, toll-like receptor 4; TNF, tumor necrosis factor; TRAF6, TNF receptor-associated factor 6; VEGFR2, vascular endothelial growth factor receptor 2.

Table III Structural modification of erianin.

Table III

Structural modification of erianin.

A, Derivatives
Name	Mechanism	Cancer	(Refs.)
Ecust 004	Upregulation of E-cadherin, α-catenin and vinculin; downregulation of SLUG	Breast	(115)
EBTP	Downregulation of PIK3R2, p-PI3K, p-AKT, VEGF-A, VEGFR1/VEGFR2 and lncRNA TMPO-AS1; upregulatio of miR-126-3p↑	Breast, cervical, colorectal, liver, lung	(116-118)
HDAC1/6 inhibitor 27f	Induces apoptosis	Lymphoma	(120)
HDAC1/6 inhibitor (39f)	Induces apoptosis; stimulates cell cycle arrest in G1 phase	Lymphoma	(120)
ZJU-6	Downregulation of Mcl-1 and Bcl-2; upregulation of PARP	Breast, colon, pancreatic	(121)
B, Analogues
ZY-444	Inhibits PC	Liver	(125)
[18F]FEE	Downregulation of EPK, JNK/c-Jun, AKT/mTOR, and MAPK signaling pathways, IDO expression, and VEGF/VEGFR2 signaling; upregulation of apoptosis, autophagy and G2/M phase cell cycle arrest.	Liver	(129)
C, Complexes
Ru(phen)2 (L1-(CH2)4-erianin)2	Increased stability of c-myc G-quadruplex	Breast, cervical, colon, small cell lung	(130)
Ru(phen)2 (L2-(CH2)4-erianin)2	Increased stability of c-myc G-quadruplex	Breast, cervical, colon, small cell lung	(130)

[i] AS1, antisense transcript 1; E-cadherin, epithelial cadherin; HDAC, histone deacetylase; Mcl-1, myeloid cell leukemia 1; lnc, long non-coding; miR-126-3p, microRNA-126-3p; PARP, poly (ADP-ribose) polymerase; PC, pyruvate carboxylase; PI3K, phosphoinositide 3-kinase; PIK3R2, phosphoinositide-3-kinase regulatory subunit 2; p-, phosphorylated; SLUG, Snail family transcriptional repressor 2; VEGFR1, vascular endothelial growth factor receptor 1.

Technological developments

Derivatives

The development of erianin derivatives has improved its anticancer efficacy and pharmacokinetic properties by structural modification. As a sulfamate derivative, Ecust 004 (Fig. S1) shows improved bioavailability and anti-breast cancer cell metastasis ability while retaining the activity of erianin and combretastatin A4 (CA4) (115). Clinically, the importance of Ecust004 lies in its dual-targeting mechanism by serving both as a tubulin and steroid sulfatase inhibitor, which effectively induces G2/M cell cycle arrest and reverses EMT, a key driver of metastasis, by upregulating E-cadherin and downregulating transcription factors such as SLUG and ZEB1 (115). However, the drug is in the preclinical experimental stage. While the sulfamate modification overcomes the obstacle of poor water solubility common in natural phenolic complexes, hurdles remain for clinical translation, including the need to address challenges associated with clinical scalability, targeting efficacy and the potential for off-target effects such as neurotoxicity and myelosuppression typically associated with tubulin inhibitors (115). Although preliminary in vivo studies have shown tumor suppression without significant weight loss in mice, extensive toxicology profiles are required to rule out off-target effects, particularly the neurotoxicity and myelosuppression typically associated with tubulin inhibitors (115). Furthermore, future research should clarify the precise molecular mechanism behind SLUG suppression and evaluate the scalability of chemical synthesis for potential pharmaceutical production (115).

Phosphorylated derivative EBTP (Fig. S2) inhibits the PI3K/Akt pathway by regulating the thymopoietin antisense RNA 1(TMPO-AS1)/miR-126-3p/PIK3R2 axis (116) and achieves VEGF/EGFR dual pathway inhibition in combination with afatinib (117). As a vascular blocker, EBTP has anti-proliferative effects and can inhibit the proliferation of breast, cervical, lung and liver cancer, as well as endothelial cells (117,118). EBTP is less toxic than CA4P, and inhibits the expression of indoleamine 2,3-dioxygenase, thereby inhibiting the migration and invasion of CRC cells (118).

From a translational perspective, EBTP represents a promising strategy for anti-angiogenic therapy. However, EBTP remains in the preclinical experimental stage. While molecular docking and RNA sequencing provide a theoretical foundation for its mechanism, obstacles regarding clinical scalability and targeting efficacy must be addressed (117). While regulating the long non-coding RNA/miRNA pathway offers high specificity, the systemic delivery of RNA-modulating drugs poses challenges, such as the risk of off-target effects, obstacles in clinical scalability, and challenges in targeting efficacy (117). Furthermore, although BALB/c nude mouse models suggest manageable toxicity, the potential off-target effects of systemic PI3K/AKT pathway inhibition in human patients require evaluation in clinical trials (117,119).

Erianin-based histone deacetylase inhibitors (HDACis) and novel S derivative ZJU-6 have shown advantages through multi-target regulation (120). By incorporating a polar HDACi pharmacophore into the β-elemene scaffold, these hybrid agents address the limitations of antitumor activity and poor solubility found in the parent natural product (120). Combined regulation of epigenetics (HDAC inhibition) and signal transduction allows enhanced therapeutic outcomes. HDAC1/6 inhibitors 27f (Fig. S3) and 39f (Fig. S4) can effectively induce apoptosis, and 39f can also stimulate cell cycle arrest in G1 phase (120). Consequently, these β-elemene-based HDACis provide an important paradigm for the development of natural product-based precise anti-lymphoma strategies, though structural optimization is required to ensure favorable pharmacokinetic profiles for clinical translation (120). ZJU-6 (Fig. S5) provides a direction for the study of pancreatic, breast and colon cancer by serving as a dual-action agent that inhibits tubulin polymerization and suppresses angiogenesis (121). However, ZJU-6 is currently in the preclinical stage. While it demonstrates superior anti-angiogenic properties and antioxidant capacity compared with erianin, it exhibits variable cytotoxicity across different cell lines (high potency in MDA-468 cells but decreased efficacy in MCF-7 cells) (121). Future research should clarify the target selectivity to overcome this sensitivity gap, evaluate in vivo mammalian toxicity and assess the combined drug potential of each derivative to determine clinical transformation feasibility.

Analogues

Erianin analogues have value in targeting the key enzyme PC of cancer metabolism. Previous studies have shown that PC, as a mitochondrial metabolic hub enzyme, is highly expressed in numerous types of cancer, such as hepatocellular carcinoma (122-124). Through the systematic structural modification of erianin, the inhibitory activity of ZY-444 (Fig. S6) on PC is increased, which provides a lead structure for the development of novel PC targeted inhibitors (125). However, the clinical transformation of ZY-444 appears to be limited. Despite its initial promise, to the best of our knowledge, no clinical trials have been reported thus far, likely due to its moderate potency compared with emerging natural product derivatives such as Ecust 004 (125). While targeting metabolic reprogramming remains a promising technology, the field faces obstacles regarding drug stability, oral bioavailability and the need for nanomolar affinity to ensure safety and efficacy (126-128).

In terms of diagnostic applications, the radiolabeled derivative [18F]FEE (Fig. S7) allows PET imaging in a HepG2 liver cancer model by retaining the PC-targeting properties of erianin (129). The aforementioned study demonstrated that [18F]FEE can be synthesized with high radiochemical purity via efficient nucleophilic substitution and exhibits favorable metabolic stability in serum. By retaining the specific properties of erianin (such as PC targeting or vascular disruption), [18F]FEE demonstrates a time-dependent increase in the tumor-to-muscle ratio, allowing for distinct visualization of tumor borders in mice (129).

However, there are hurdles for clinical translation. Although the synthetic method is established and scalable, pharmacokinetics poses a challenge (129). Due to liver clearance, the uptake of tracers in tumors is not notably different from that in surrounding liver tissue (129). This high background signal is a significant obstacle for diagnosing primary hepatocellular carcinoma, potentially limiting the utility to extrahepatic metastases unless structural modifications alter its excretion pathway (129). Additionally, while analogues remain cytotoxic, the technology remains in the experimental preclinical stage, and issues regarding potential systemic toxicity and precise molecular binding specificity in humans remain unverified (125,129).

Despite these limitations, the aforementioned studies have established a dual-pathway clinical application framework of erianin analogues, including the development of therapeutic inhibitors based on PC targets and molecular imaging evaluation of PC expression levels. This strategy not only provides a potential candidate drug for the treatment of liver cancer, but may facilitate early diagnosis and efficacy monitoring of tumors, and has clinical transformation prospects. Future studies should verify the in vivo safety and target specificity of these analogues.

Complexes

The erianin-ruthenium (II) complex shows anticancer potential in the targeted regulation of G-quadruplex DNA (G4 DNA), which provides a novel concept for the study of breast, colon and cervical cancer and SCLC (130). Binding affinity and structural stability of complexes 1 and 2 formed by the coordination of erianin with ruthenium (II) (130) with G4 DNA in the promoter region of the c-myc gene are significantly enhanced. Complex 1 is Ru(phen)2(L1-(CH2)4-erianin)2 (Fig. S8), while complex 2 is Ru(phen)2(L2-(CH2)4-erianin)2 (Fig. S9). These complexes stabilize the advanced structure of c-myc G4 DNA through specific external binding and effectively inhibit the transcriptional expression of the c-myc proto-oncogene at the molecular level (130). The aforementioned study adopted a 'hybrid ligand' strategy, using erianin to enhance the targeting specificity of metal complexes. Complex 2 increases the melting temperature of c-myc G4 DNA by 16.5°C and exerts transcriptional inhibition by inserting into the narrow groove of DNA (the T19-A24 base pair region) (130). This provides novel insights for the development of epigenetically targeted drugs (130). However, technology remains in its early stages, and clinical translation faces multiple challenges, including lack of in vivo efficacy and metabolism validation and the need to improve selective recognition of c-myc G4 structures to avoid off-target toxicity. To the best of our knowledge, systemic toxicity, accumulation and metabolic stability have not been clearly defined and there are complex synthesis processes, high costs for large-scale production and stringent quality control requirements. Therefore, although complex 2 is a promising lead complex, future research should evaluate its pharmacokinetic properties in biological systems and overcome the technical bottlenecks associated with its transmembrane delivery and intracellular targeting. These findings not only provide a direction for the development of novel anticancer drugs based on epigenetic regulation, but also offer strategies to address the non-specific cytotoxicity associated with traditional chemotherapeutic agents.

Drug carrier modification

Nano-delivery system

The development of an erianin nano-delivery system has improved the clinical application bottleneck of this natural product. Solubility, targeting and therapeutic effect of erianin have been improved through preparation techniques (131). In cancer therapy, the DOX and erianin-loaded CaCO3-based nanoparticles (DECaNPs) system shows multiple advantages, such as inducing calcium overload, neutralizing the acidic tumor microenvironment, activating oxidative stress damage, promoting immunogenic cell death, and enhancing immunotherapy (132). Similarly, the curcumin encapsulated nanoparticles (CEN) system combined with celastrol and erianin through self-assembly technology (133), shows benefits including enhancing cancer accumulation, improving drug solubility, and reduced systemic toxicity while maintaining potent anticancer activity. In the treatment of skin disease, the embedded dual-mesoporous silica nanoparticles (E/DMSNs) system enhances the inhibitory effect on keratinocytes through mitochondrial and endoplasmic reticulum stress pathways (134) and the light-responsive carrier achieves controlled release delivery of erianin (131).

Nano-delivery system solves the core problems of poor water solubility and low bioavailability of erianin (131). However, this technology faces three major challenges, including the balance between preparation stability and drug loading efficiency, optimization of large-scale production process and verification of long-term safety. Future research should aim to overcome these technical bottlenecks while maintaining targeted advantages to accelerate the clinical transformation of erianin nanoformulations.

Liposome delivery system

The erianin liposome delivery system provides an effective strategy to solve the poor aqueous solubility and off-target effects in its clinical application. Previous studies have shown that the solubility and targeting of erianin are improved by folic acid-chitosan modified dual drug-loaded liposomes (135) and transferrin-coupled liposomes (Tf-LP-ERN) (136). These systems enhance the accumulation of drugs in cancer cells through specific ligand-receptor interactions (such as folate receptor and transferrin receptor-mediated endocytosis), while using the sustained release characteristics of liposomes to prolong drug efficacy (136-138).

Although the liposome delivery system has good biocompatibility and high safety, it faces challenges, including complex preparation processes leading to batch-to-batch differences, poor physical stability affecting the storage period and high production costs restricting industrial production (136-138). Overcoming these technical bottlenecks is required to achieve the clinical application of erianin liposome preparations. In summary, carrier modification technology has a range of applications in erianin through nano-delivery and liposome delivery systems (Fig. 6).

Figure 6 Nano-delivery systems and liposome-based carriers for erianin. (A) Nano-delivery systems (DECaNPs, CEN, E/DMSNs and photoresponsive dendritic mesoporous silica nanoparticle carriers) are designed to co-deliver erianin with chemotherapeutic agents. These systems enhance cancer accumulation, ameliorate the acidic microenvironment and promote systemic anticancer immunity. (B) Ligand-modified liposomal carriers (double drug-loaded liposomes system and Tf-LP-ERN) improve erianin solubility and targeting via receptor-mediated endocytosis. These liposomes exhibit sustained release and enhance drug accumulation at the disease site. DECaNP, doxorubicin and erianin-loaded CaCO3-based nanoparticles; CEN, curcumin encapsulated nanoparticles; E/DMSN, embedded dual-mesoporous silica nanoparticles; Tf-LP-ERN, transferrin-conjugated liposome loaded with erianin; SP, substance P; APTES, 3-aminopropyltriethoxysilane; PFDTES, perfluorodecyltriethoxysilane.

Metabolism and practical application

The metabolic study of erianin provides a pharmacological basis for its clinical application. A total of 24 metabolites have been identified in vitro and in vivo by liquid chromatography/ultraviolet/mass spectrometry (138). The aforementioned study revealed that erianin undergoes extensive biotransformation involving specific pathways (hydroxylation, demethylation, and dehydrogenation in phase I; glucuronidation, glutathione, and N-acetylcysteine conjugation in phase II) and enzyme systems [cytochrome P450 (CYP) and uridine diphosphate-glucuronosyltransferases (UGTs)]. Metabolism is performed through different phase I and phase II reaction pathways. Previous metabolic studies have shown that erianin undergoes a complex biotransformation process (5,7). Hydroxylation, demethylation and dehydrogenation reactions mainly occur in phase I metabolism. These reactions are may be mediated by cytochrome P450 (CYP) enzymes that convert lipophilic prototype drugs into more polar intermediates (7,139). A key step involves the partial demethylation of trimethoxyphenyl to form a catechol group, which is unstable. In phase II metabolism, these reactive intermediates primarily combine with glutathione (GSH), glucuronic acid and N-acetylcysteine. The primary pathways differ depending on the species and substrate (7,139). In human liver cells and rat urine, glucuronidation (particularly metabolite M19) is the main detoxification pathway. GSH binding (metabolite M6) is the most abundant in rat bile, indicating significant bile excretion of reactive conjugates. These metabolic reactions change the physicochemical properties of erianin (7,139).

Extensive first-pass metabolism in hepatocytes is the primary reason for the low oral bioavailability and short half-life of erianin. Its glucuronide conjugates are readily excreted via the kidney due to their high polarity, while GSH conjugates are primarily cleared through bile (7,139). Catechol intermediates generated during metabolism are oxidized to reactive ortho-benzoquinones, which, as electrophilic complexes, bind intracellular nucleophiles (7,139). The detection of abundant GSH/n-acetylcysteine conjugates in vivo indicates that these reactive intermediates are captured by the antioxidant system (7,139). Although quinone metabolites typically carry the risk of hepatotoxicity, previous studies have found that glucuronidation competes with this bioactivation pathway, forming a detoxification mechanism, which may be an important reason for its clinical safety profile (7,139).

In summary, the metabolism of erianin reflects a dynamic balance between the formation of reactive quinones (captured via GSH) and UGT-mediated glucuronide detoxification. Future studies should identify the relevant CYP/UGT subtypes to assess the risk of drug-drug interactions and validate the safety threshold for quinone formation and detoxification capacity in humans.

These metabolic characteristics are key for understanding the efficacy and safety of erianin. The diversity of metabolites suggests it may exert pharmacological effects through multiple pathways. GSH binding may be related to its antioxidant and cytoprotective effects (140-142). Glucuronidation affects its bioavailability and clearance rate (139). However, research on the activity of metabolites remains insufficient. It is necessary to clarify the pharmacological activity and toxicity characteristics of the primary metabolites in order to provide a more comprehensive scientific basis for the clinical rational use of erianin.

Biosynthesis and large-scale production

Systematic breakthroughs have been made in the research on the biosynthesis mechanism and large-scale production technology of erianin. A total of 11 key genes involved in bibenzyl synthesis in D. officinale has been identified (143) and the catalytic divergence mechanism of O-methyltransferase in p-methoxybenzyl synthesis has been demonstrated (144). A previous multi-omics integration study analyzed the complete biosynthetic pathway from gigantol (Fig. S10) to erianin (145), providing a key target for metabolic engineering. In terms of optimization of the extraction process, the petroleum ether extraction method shows industrial potential due to its high purity (146).

An economical and efficient route for the synthesis of erianin has been established: Using homovanillic acid and 3,4,5-trimethoxybenzaldehyde as starting materials, through the integrated process of hydroxyaldehyde condensation-microwave-assisted decarboxylation-mild reduction (147), the high cost and cumbersome steps in traditional synthesis has been solved.

The aforementioned studies have established the production system of erianin biosynthesis-chemical synthesis-extraction and purification, which provides a foundation for promoting its clinical application. Future research should focus on solving key issues such as the improvement of biosynthesis efficiency and the scale of extraction to accelerate the industrialization process.

Traditional production methods for erianin face a dual challenge: Scarcity of raw materials and the limitations of synthetic chemistry. Natural extraction from D. chrysotoxum is inefficient due to low yields (0.12%), creating a bottleneck for extensive applications. Furthermore, chemical synthesis is unsustainable due to its high economic cost and environmental footprint. These factors highlight a need to uncover the biosynthetic mechanisms for erianin production, thereby enabling the development of environmentally friendly biosynthetic manufacturing processes (145).

In summary, erianin has a wide range of pharmacological activities. The problems of poor water solubility and low bioavailability of erianin have been solved by chemical modification, preparation techniques and structural optimization and expanded to preclinical research, biosynthesis and large-scale production (Fig. 7).

Figure 7 Research overview of erianin. (A) Erianin has a wide range of pharmacological activities. (B) Erianin exhibits poor water solubility and low bioavailability. (C) Derivatives, analogues and complexes have been designed by structural modification. (D) Synthesis of erianin from gigantol provides a theoretical basis for the biosynthesis and large-scale production industrialization of erianin.

Discussion

The natural product erianin has a range of pharmacological activities, most notably broad-spectrum anticancer effects by regulating multiple core signaling pathways and targets, such as the PI3K/AKT/mTOR, JAK/STAT, MAPK, and Wnt/β-catenin pathways. Previous studies focused on its pharmacological activity (5-7). In recent years, erianin has been found to have poor water solubility and low bioavailability, which limits its application as an anticancer drug (7). Therefore, methods such as structural and carrier modifications are being explored to promote the application of erianin. Structure-dependent activity and preclinical and clinical studies are essential to elucidate its pharmacokinetic characteristics and bioavailability (115,116,120).

The present review aimed to demonstrate pharmacological properties of erianin and establish a systematic paradigm for natural product drug research. This paradigm emphasizes a shift from the discovery of single active ingredients to multidimensional mechanistic analysis and the design of a full-chain pipeline leading to clinical translation. The transition of erianin from a traditional phytochemical to a potent lead complex exemplifies this paradigm.

Unlike conventional chemotherapeutic agents that typically rely on a single cytotoxic mode (DNA alkylation or tubulin inhibition), erianin exhibits pleiotropic pharmacological characteristics (5-7). By simultaneously orchestrating ferroptosis via the system xc-/GPX4 pathway (45,46), inducing mitochondrial apoptosis (20,26,47,54) and disrupting the tumor microenvironment (61) through anti-angiogenesis and immune modulation, erianin addresses the inherent heterogeneity of solid tumors. This multi-target strategy is advantageous in overcoming MDR, a prevalent problem in oncology. For example, the ability of erianin to downregulate P-gp while inducing ferroptosis suggests that it may be effective in refractory cancer cases where the apoptotic machinery is compromised (108).

To assess the potential of erianin it is necessary to compare its profile against established therapies. Conventional targeted therapies (tyrosine kinase inhibitors) (148,149) are typically limited by the rapid emergence of bypass signaling mutations. Erianin-induced broader inhibition of converging downstream hubs (PI3K/AKT/mTOR and MAPK) may create a higher barrier to resistance (23). However, compared with highly specific monoclonal antibodies, this polypharmacology introduces a risk of off-target toxicity, indicating that efficacy and safety must be balanced (150).

Compared with other natural products such as paclitaxel (151) or vincristine (152), erianin shares microtubule-destabilizing properties (109) but also exerts metabolic reprogramming (suppression of aerobic glycolysis and lipid metabolism) (7,139). However, erianin currently lags behind these established agents in pharmaceutical development. While the solubility issues of paclitaxel have been addressed through formulation strategies, erianin remains in the early stages of formulation optimization. The formation of reactive quinone metabolites identified in metabolic studies poses a risk of unpredictable hepatotoxicity similar to that observed with other phenol-containing drugs (such as acetaminophen), necessitating rigorous benefit-risk assessments currently absent in the clinical literature. This druggability assessment requires confronting physicochemical defects and metabolic risks in addition to focusing on activity (7,139).

Despite promising preclinical data, the disparity between laboratory findings and clinical application remains an obstacle for erianin. The primary barriers are physicochemical (poor solubility) and pharmacokinetic (rapid metabolic clearance via glucuronidation) (7). The technological advancements reviewed in the present study, specifically the development of sulfamate (Ecust004) (115) and phosphate (EBTP) derivatives (118), demonstrate that structural modification can improve bioavailability without sacrificing potency. However, compared with the extraction of the parental complex, the reliance on chemical synthesis for these derivatives introduces complexity. Furthermore, the emergence of ruthenium-erianin complexes represents a paradigm shift from cytotoxicity to epigenetic modulation (stabilizing G4 DNA) (130). These strategies demonstrate how technological methods overcome the inherent limitations of natural products (7).

The lack of clinical data for erianin should be addressed not through broad-spectrum trials but via a precision medicine approach informed by the mechanistic insights highlighted in the present review. Based on preclinical evidence regarding ferroptosis and metabolic regulation, early-phase clinical trials should prioritize hepatocellular carcinoma and TNBC (22,24,49). Hepatocellular carcinoma is characterized by high iron load and metabolic dysregulation, making it susceptible to erianin-induced ferroptosis and GPX4 inhibition (22,24). Similarly, the aggressive, metastatic nature of TNBC aligns with the capacity of erianin to reverse EMT and inhibit metastasis (50). To maximize clinical success rates, patient selection should use biomarkers identified in mechanistic studies. High expression of SLC7A11 or GPX4 may serve as predictive biomarkers for sensitivity to erianin, while SLC40A1 levels may indicate susceptibility to iron-dependent cell death (22). Future drug development should focus on the balance between metabolic activation and detoxification. Clinical dosing regimens should be informed by quantitative pharmacology that accounts for the saturation of glucuronidation pathways. Furthermore, the development of sustained-release nanoformulations (such as the Tf-LP-ERN system) is key for maintaining therapeutic plasma concentrations and avoiding high fluctuations that may exacerbate toxicity (136). This roadmap constructs the clinical translation pathway, emphasizing a framework from mechanism to indication and from biomarkers to formulation optimization.

In conclusion, erianin represents a versatile chemical scaffold with the potential to address unmet needs in oncology and chronic inflammation. A shift from descriptive pharmacological studies to rigorous pharmacokinetic optimization and biomarker-guided translational trials is required.

Conclusion

Natural products have been widely used in the treatment of various diseases. Erianin is a low molecular weight natural product isolated from D. chrysotoxum, which has a wide range of pharmacological activities. The present study aimed to comprehensively review erianin, solving practical problems through chemical modification, preparation technology and structural optimization, and extends to preclinical research, biosynthesis and large-scale production.

Future studies on the design and synthesis of erianin derivatives may facilitate development of new drugs with improved pharmacological properties. In addition, the in vitro synthesis process of erianin is well-established (143-147), and its extensive pharmacological activity has also been verified (5-7). However, the structural modification and functional preparation of erianin are in the exploratory stage. A key direction of future research is to decrease the toxicity of erianin in vivo and maximize its efficacy at specific sites.

Supplementary Data

Availability of data and materials

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Authors' contributions

CM wrote the manuscript and constructed figures. NZ, YY, HZ and MH wrote and editing the manuscript. Data authentication is not applicable. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

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Patient consent for publication

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Competing interests

The authors declare that they have no competing interests.

Acknowledgements

Not applicable.

Funding

The present study was supported by the Hubei Provincial Natural Science Foundation and Xianning of China (grant no. 2025AFD393), the Science and Technology Research Project of Hubei Education Department (grant no. T2023024) and the Medical Scientific Research Project of Hubei University of Science and Technology (grant no. 2022YKY08).

References