ANGPTL4 exhibits varied regulatory effects across different types of tumors. Ding et al (32) demonstrated that the recombinant ANGPTL4 protein reduces CD8⁺ T cell infiltration and activation through metabolic reprogramming, thereby diminishing immune surveillance during tumor progression and facilitating tumor growth in vivo. In breast tumors of obese mice, ANGPTL4 expression has been shown upregulated, and the suppression of ANGPTL4 leads to a significant reduction in obesity-induced tumor growth (33). Interleukin-1β (IL-1β) in primary adipocytes stimulates ANGPTL4 expression through the activation of nuclear factor-κ B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, with hypoxia further enhancing IL-1β expression (33). This indicates that ANGPTL4 mediates the crosstalk between obesity-associated inflammation and BRC progression. Avalle et al (34) found that cancer-associated fibroblasts (CAFs) promote tumor growth in BRC, with signal transducer and activator of transcription 3 (STAT3) amplifying the effects of CAFs via ANGPTL4. In ovarian cancer (OVC), ANGPTL4 was significantly upregulated in clinical samples and correlated with poor prognosis (35). ANGPTL4 promotes OVC progression by activating the Janus kinase 2 (JAK2)/STAT3 pathway (35). Xu et al (36) further demonstrated that ANGPTL4 enhances ovarian tumor cell proliferation through the extracellular signal-related kinase (ERK) pathway, and its inhibition can suppress OVC progression via phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) (37). Additionally, several studies have shown that ANGPTL4 accelerates the proliferation and progression of numerous types of malignancies, including CRC (38), GC (39), hepatocellular carcinoma (HCC) (40,41), lung adenocarcinoma (42,43), osteosarcoma (OS) (44), thyroid cancer (45) and melanoma (46).

However, some studies suggest that ANGPTL4 may function as a tumor suppressor. Hsieh et al (47) reported the dual roles of ANGPTL4 in urothelial carcinoma (UC), showing that ANGPTL4 mRNA expression is decreased in UC cells and tumor tissues compared with adjacent normal bladder epithelial cells. Overexpression of ANGPTL4 inhibits UC cell proliferation both in vivo and in vitro (47). Hui et al (48) found that long non-coding RNA (lncRNA) AGAP2-AS1 downregulates ANGPTL4 expression through its interaction with the enhancer of zeste homolog 2 (EZH2), thereby promoting the proliferation and metastasis of pancreatic cancer. A negative correlation between the expression of ANGPTL4 and OS progression has also been observed (49). Knocking out ANGPTL4 in OS cells leads to the accumulation of branched-chain amino acids (BCAAs), which activates the mechanistic target of rapamycin (mTOR) signaling pathway and enhances OS cell proliferation (49). In addition, homeobox transcription factor 1α (LMX1A) has been shown to suppress tumor growth by activating ANGPTL4 to hinder c-Myc in GC (50). The negative regulatory effects of ANGPTL4 on tumor growth have also been reported in renal clear cell carcinoma (51) and CRC (52).

Metastasis refers to the spread of malignant cells to distant organs, and it is often the primary cause of mortality in most cancers, as metastatic cancer cells typically exhibit high invasiveness and resistance to anticancer therapies. It has been indicated that ANGPTL4 plays a crucial role in cancer invasion and metastasis processes.

Hübers et al (53) identified cANGPTL4 and nANGPTL4 as pro- and antitumor contributors, respectively, in the bidirectional communication between primary tumors and distant metastases. It was observed that cANGPTL4 promotes tumor growth and metastasis, while nANGPTL4 inhibits metastasis and improves overall survival by suppressing Wnt signaling and reducing vascular distribution at metastasis sites. These findings suggested that cANGPTL4 could serve as a potential biomarker for tumor progression and a target for anti-meta-static therapy.

In BRC, HIF-2 induces the expression of the lncRNA RAB11B-AS1, which facilitates brain metastasis through the promotion of ANGPTL4 (54). Silencing ANGPTL4 in triple-negative BRC (TNBC) cells has been shown to reduce the metastatic growth of brain tumors in vivo (31). Tumor cells secrete IL-1β and tumor necrosis factor-α (TNF-α), which communicate with astrocytes, leading to increased expression of transforming growth factor-β2 (TGF-β2) and promoting the brain metastasis via the TGF-β2/ANGPTL4 axis (31). These findings provide a theoretical basis for targeting ANGPTL4 in the treatment of BRC metastasis.

In CRC, ANGPTL4 plays a role in metastasis through various mechanisms. Shen et al (55) found that NADPH oxidase 4 (NOX4)/reactive oxygen species (ROS) axis is crucial for CRC metastasis induced by oleic acid (OA). Downregulation of ANGPTL4 leads to the suppression of NOX4, ROS, matrix metalloproteinase-1 (MMP-1) and MMP-9, thus inhibiting OA-induced CRC metastasis (55). Furthermore, the metastasis in KRAS/p53 mutant CRC has been shown to depend on the activation of the ANGPTL4/IL-8/NOX4 axis (56), underscoring the importance of the ANGPTL4/NOX4 signaling axis in dyslipidemia-related and KRAS/p53 mutant CRC metastasis. Zhu et al (30) focused on the peritoneal metastasis of CRC. They reported that adipose-derived stem cells (ADSCs) secrete TGF-β1 to activate Smad3 in CRC cells, which enhances ANGPTL4 transcription. The upregulation of ANGPTL4 increases the anoikis resistance, facilitating CRC cell survival in the peritoneum and promoting metastatic foci formation (30).

Bajwa et al (57) reported that ANGPTL4, derived from cancer-associated mesothelial cells, promotes the early-stage OVC metastasis through the interactions between mesothelial cells and the tumor microenvironment (TME). Additionally, Hefni et al (58) found that ANGPTL4 induces the migration of head and neck squamous cell carcinoma (HNSCC) cells via the neuropilin1/ABL1/paxillin pathway. Similarly, ANGPTL4 has been implicated in the invasion and metastasis of lung cancer (42,59), with studies showing that modified Bu Fei decoction inhibits the metastasis of non-small cell lung cancer (NSCLC) by suppressing ANGPTL4 expression in endothelial cells (59).

Previous studies have highlighted the pivotal role of the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway in promoting metastasis through ANGPTL4. In GC, leptin induces the phosphorylation of ANGPTL4 at the serine 30 residue, reducing its binding affinity to lipoprotein lipase (LPL), thus enhancing lipid uptake and intracellular arachidonic acid levels. This accumulation subsequently activates the COX-2/PGE2 pathway, promoting lymph node metastasis (60). Moreover, Chiang et al (61) demonstrated that the COX-2/PGE2/ANGPTL4 axis, activated by epidermal growth factor (EGF), enhances metastasis in HNSCC, with PGE2 promoting ANGPTL4 expression through the ERK pathway.

Despite the general role of ANGPTL4 in promoting metastasis, some studies have identified its inhibitory effects. Overexpression of ANGPTL4 has been found to inhibit the adhesion, migration and invasion of TNBC cells in vitro, with positive correlations to favorable outcomes in patients with TNBC (62). Moreover, lncRNA AGAP2-AS1 epigenetically inhibits ANKRD1 and ANGPTL4 expression by recruiting EZH2, promoting pancreatic cancer metastasis (48). In CRC, DNA methylation-mediated downregulation of ANGPTL4 activates CAFs in the TME, promoting epithelial-mesenchymal transition (EMT) through the ERK signaling pathway, which leads to metastasis (63). In vivo experiments also revealed that overexpression of ANGPTL4 inhibits lung metastasis in CRC models (63). Additionally, inhibitory effects of ANGPTL4 on tumor metastasis have been also observed in OS (64).

Angiogenesis and increased vascular permeability are ubiquitous characteristics of all solid tumors. Therefore, research on the role of ANGPTL4 in cancer angiogenesis holds significant potential to profoundly enhance our comprehension of cancer pathogenesis and inform the development of therapeutic strategies.

Wu et al (37) found that the pro-angiogenic effects of ANGPTL4 in OVC are mediated via its association with VEGF2. Similarly, Li et al (35) discovered that ANGPTL4 enhances angiogenesis in ovarian serous cystadenocarcinoma by activating the JAK2/STAT3 signaling pathway. The mechanism is potentially due to the interaction among ANGPTL4, endothelial cell specific molecule 1 and the TME (35). ANGPTL4 has also been reported to exert pro-angiogenic effects in malignant glioma cells (65). Knockdown of ANGPTL4 significantly reduces microvascular density in xenograft tumors and inhibits tumor growth (65). Additionally, EGF receptor (EGFR) variant III induces ANGPTL4 expression through the ERK/c-Myc pathway to regulate angiogenesis (65). In Kaposi's sarcoma, the upregulation of ANGPTL4 by viral G protein-coupled receptors has been shown to enhance tumor angiogenesis and vascular permeability through the Rho/Rho-associated kinase pathway (66). The complementary effect on VEGF, a potent angiogenic factor, has also been confirmed (66). Furthermore, ANGPTL4 has exhibited a stimulatory effect on tumor angiogenesis in various cancer types, including BRC (33), uveal melanoma (67), NSCLC (68) and OS (69).

The inhibitory effects of ANGPTL4 on angiogenesis are partially attributed to its suppression of the ERK signaling pathway and post-translational modifications. Tumor-derived ANGPTL4 has been found to inhibit the angiogenesis and proliferation of umbilical endothelial cells by suppressing ERK signaling (70). The inactivation of ANGPTL4 through genetic and epigenetic mechanisms, such as hypermethylation of CpG islands in the promoter region, causes an increase in tumor growth and angiogenesis in GC (70). Yang et al (71) reported that N-glycosylated cANGPTL4 exerts an inhibitory effect on the Raf/MEK/ERK signaling cascade in endothelial cells, which suppresses the angiogenesis induced by alkaline fibroblast growth factor and VEGF. Furthermore, The inhibitory effects of ANGPTL4 on angiogenesis have also been observed in CRC (52) and HCC (72), reinforcing its potential as a modulator of angiogenesis across various cancer types.

PCD is a widespread mechanism in living organisms, essential for maintaining cellular homeostasis, development, immunity and stress response (73). PCD is regulated by numerous evolutionarily conserved pathways and well-characterized mechanisms of action (74). Based on specific morphological, immunological and genetic characteristics, PCD can be classified into several forms, including apoptosis, ferroptosis, necroptosis, pyroptosis and autophagy-dependent cell death (75,76). PCD is crucial in tumor suppression through its involvement in anticancer therapies. In the present review, the interactions between various forms of PCD and ANGPTL4 in cancer are discussed.

Apoptosis, the most extensively studied form of PCD, was first described by Kerr et al in 1972 (77). Apoptosis relies on a cascade of caspase proteases and can be initiated via extrinsic or intrinsic pathways (78). As early as the 1970s, studies demonstrated that apoptosis is crucial for eliminating potentially malignant cells, controlling hyperplasia, and inhibiting tumor progression (79). The induction of apoptosis is fundamental in cancer therapy. The dual role of ANGPTL4 in regulating tumor cell apoptosis has been reported.

Lim et al (80) reported the anti-apoptotic effect of ANGPTL4 and observed that inhibiting ANGPTL4 leads to the accumulation of chemotherapy drugs in cells, thereby inducing apoptosis. The mechanism involves reduced energy production and accumulation in cancer cells and the weakened drug efflux during EMT. In HCC (81), ANGPTL4 knockout cell lines exhibited significantly higher levels of apoptosis. Bai et al (41) further investigated the role of different ANGPTL4 transcripts and found a notable increase in ANGPTL4-Transcript 3 expression in HCC tissues. The overexpression of ANGPTL4-Transcript 3 significantly confers apoptosis resistance to HCC cells, whereas Transcript 1 has no such effects (41). Fang et al (43) conducted a study on the role of ANGPTL4 in regulating gefitinib resistance in NSCLC cells. The aforementioned study demonstrated that ANGPTL4 is crucial in inhibiting cell apoptosis by suppressing the NOD-like receptor family, pyrin domain containing 3 (NLRP3)/apoptosis-associated Speck-like protein (ASC)/caspase-8 pathway, thereby enhancing resistance to gefitinib (43). ANGPTL4 also enhances the apoptosis resistance in CRC (38,82). Knocking down bone morphogenetic protein 7 (BMP7) reverses the anti-apoptotic effect of ANGPTL4 overexpression, suggesting that ANGPTL4 may inhibit apoptosis in CRC cells by upregulating BMP7 (82).

Most studies to date have highlighted the anti-apoptotic effect of ANGPTL4 in tumors. However, Hsieh et al (83) reported the pro-apoptotic effect of ANGPTL4 in UC. Cyproheptadine was found to upregulate ANGPTL4 expression and activate apoptosis-related proteins such as caspase-3 and poly (ADP-ribose) polymerase (PARP), thereby promoting apoptosis and inhibiting the growth of UC cells. This process might involve the regulation of glycogen synthase kinase 3β (GSK3β)/tuberous sclerosis complex subunit 2 (TSC2)/mTOR and GSK3β/β-catenin signaling pathways.

Anoikis is a specialized form of apoptosis that occurs when cells detach from the surrounding cellular or extracellular matrix (ECM) (84,85). However, tumor cells can develop resistance to anoikis, enabling them to evade cell death and continue proliferating after detachment. Anoikis resistance facilitates immune evasion, alters the TME, and ultimately contributes to the invasion and metastasis (85,86).

In HNSCC, EGF induces ANGPTL4 expression, significantly enhancing anoikis resistance, and promoting migration and invasion (87). This effect is mediated through the expression of MMPs, particularly MMP-1, as regulated by ANGPTL4 (87). Shen et al (88) discovered that OA induces ANGPTL4 expression in HNSCC, which significantly enhances the anoikis resistance by upregulating Ras-related C3 botulinum toxin substrate 1 (Rac1)/cell division control protein 42 (Cdc42) and MMP-9 pathways, thus promoting tumor metastasis.

Zhu et al (89) found that ANGPTL4 secreted by tumors specifically binds to integrins β1 and β5, leading to the activation of focal adhesion kinase (FAK) and Rac1. This activation increases the O2-: H2O2 ratio, subsequently activating the Src, which triggers the phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) pathways, resulting in the resistance to anoikis (89). Similarly, in GC, ANGPTL4 inhibits the occurrence of anoikis by regulating the focal FAK/Src/PI3K-AKT/ERK pathway and suppressing caspases-3, -8, and -9 (90).

During the peritoneal metastasis of CRC, ADSCs enhance the anoikis resistance of CRC cells through the TGF-β1/Smad3/ANGPTL4 axis (30). Additionally, Hao et al (59) demonstrated that the downregulation of ANGPTL4 weakens the endothelial barrier disruption and promotes anoikis in lung cancer. Furthermore, the overexpression of ANGPTL4 is closely associated with anoikis resistance in cholangiocarcinoma (91), HCC (92) and uveal melanoma (93).

These findings provide new insights into the mechanisms of metastasis, suggesting that ANGPTL4 may serve as a promising therapeutic target for intervening in anoikis and tumor metastasis. The FAK/Src/PI3K-AKT/ERK pathway, along with MMPs, is the key mediator of anoikis regulated by ANGPTL4.

Ferroptosis, an iron-dependent form of cell death, is characterized by excessive iron accumulation, lipid peroxidation and cell membrane rupture (94,95). It can be triggered via the inhibition of intracellular antioxidant enzymes such as glutathione peroxidase 4 (GPX4) (96,97). Ferroptosis has been identified as a key mechanism in tumor development and radiation respons (98-100).

Zhang et al (101) uncovered the molecular function of ANGPTL4 in hypoxic TME and proposed that hypoxia-induced ANGPTL4 contributes to radiotherapy resistance in NSCLC by regulating ferroptosis. Under hypoxic conditions, the expression of ANGPTL4 is significantly upregulated in NSCLC cells and can be enriched in extracellular vesicles, which can be transferred to adjacent normoxic cells (101). Both in vivo and in vitro experiments have confirmed that ANGPTL4 inhibits ferroptosis by regulating radiation-induced lipid peroxidation and the expression of hallmark ferroptosis proteins, such as GPX4 and ferritin heavy chain 1 (101).

By contrast, Yang et al (102) reported the opposite effect in OVC. The study identified ANGPTL4 as a direct target gene of transcriptional coactivator with PDZ binding motif (TAZ) through the integrated genomic analysis (102). The upregulation of ANGPTL4 activated NADPH oxidase 2 (NOX2) in vitro, thereby increasing the sensitivity to ferroptosis (102).

Pyroptosis is a previously identified form of PCD characterized by immune responses and inflammation (103,104). As a critical innate immune response, pyroptosis induces immune phagocytosis to counter infections and endogenous threats (105-107). Pyroptosis is triggered by caspase-1, -4, -5 and -11, and activated by inflammasomes such as NLRP3 (108-110).

The role of ANGPTL4 in pyroptosis has been reported in sepsis-induced acute lung injury, where its knockdown was shown to inhibit macrophage M1 polarization and pyroptosis, thereby providing a protective effect (111). In a study by Fang et al (43), ANGPTL4 was found to be highly expressed in lung adenocarcinoma cells, and its knockdown leads to increased pyroptosis via the NLRP3/apoptosis-associated speck-like protein containing a CARD (ASC)/Caspase-8 signaling pathway (43). Currently, the research on the regulation of tumor pyroptosis by ANGPTL4 is limited, and further studies are needed to clarify its precise role in the pyroptosis of tumor cells.

Metabolism is a fundamental biological activity intrinsic to all organisms, reflecting the processes of matter and energy transformation. The rapid proliferation and high energy demand of tumor cells lead to the significant metabolic alterations, which provide a biochemical basis and directly promote tumorigenicity and malignancy (112-116). The metabolic reprogramming of glucose, lipids and amino acids, three major functional biomolecules, enables tumor cells to acquire energy through various pathways, supporting their uncontrolled proliferation and survival. Targeting these metabolic pathways has become a promising anticancer strategy.

Glucose is the most critical energy source for living organisms, and its metabolic pathways include glycolysis, the pentose phosphate pathway and oxidative phosphorylation. Even in the presence of oxygen, tumor cells predominantly produce ATP through glycolysis, a phenomenon known as aerobic glycolysis or the Warburg effect (117,118). Aerobic glycolysis is crucial for the proliferation, growth, invasion and treatment of cancer (119).

In recent years, an increasing number of studies have shown that ANGPTL4 plays a significant role in tumor aerobic glycolysis. Zheng et al (120) found that in Fusobacterium nucleatum-infected CRC cells, increased acetylation of histone H3 lysine 27 upregulates the expression of ANGPTL4. ANGPTL4 promotes glucose uptake and aerobic glycolysis in CRC cells both in vitro and in vivo, which in turn enhances Fusobacterium nucleatum colonization. This effect is mediated by ANGPTL4's regulation of glucose transporter-1 (GLUT-1), thereby promoting the development, metastasis and chemoresistance of CRC. Similarly, in a study by Mizuno et al (121), it has been shown that ANGPTL4 affects the expression of GLUT-1 and GLUT-3 in CRC, and is associated with glucose metabolism activity and cancer progression. These studies indicate that GLUTs, particularly GLUT-1, is a key molecule in ANGPTL4-mediated regulation of aerobic glycolysis. Additionally, ADSCs derived from fat tissues have been shown to promote glycolysis in CRC cells through the TGF-β1/Smad3/ANGPTL4 axis, ultimately facilitating peritoneal metastasis (30). Overall, ANGPTL4 serves as a key target for regulating aerobic glycolysis and tumor progression in CRC.

At present, most research on the regulation of glucose metabolic reprogramming by ANGPTL4 has focused on CRC, and its regulatory roles and associated molecular mechanisms in other tumors require further investigations.

Reprogramming of lipid metabolism is a newly recognized hallmark of malignancy (122,123). Increased lipid uptake, storage and lipogenesis are observed in various cancers and contribute to accelerated tumor growth (124-127). ANGPTL4, as a lipid regulatory factor, has been widely reported for its role in lipid metabolism, particularly its effects on LPL (7,14,128-131).

Numerous studies have demonstrated the close association between ANGPTL4 and lipid metabolism in tumors. In GC, Xiao et al (60) discovered that leptin induces the phosphorylation of the serine 30 residue of ANGPTL4, thereby reducing its binding affinity with LPL. This reduction promotes LPL-mediated lipid uptake and increases intracellular arachidonic acid levels, disrupting cellular lipid homeostasis, and triggering the COX-2/PGE2 pathway. Consequently, this process promotes tumor lymphangiogenesis and lymph node metastasis in GC. Xiao et al (132) reported that ANGPTL4 significantly affects fatty acid oxidation and promotes energy generation in NSCLC cells, which may be achieved through carnitine palmitoyl-transferase 1 (CPT1). Hu et al (42) identified ANGPTL4 as a direct target of miR-133a-3p, with its expression significantly accelerating lipid metabolism in lung adenocarcinoma.

ANGPTL4 also mediates the metabolic crosstalk between tumor cells and adipocytes. Blücher et al (133) demonstrated that adipose tissue secretory factors reprogram tumor lipid metabolism and induce motility by regulating PPAR α/ANGPTL4 and FAK in TNBC cells, with ANGPTL4 identified as the key factor in lipid metabolism regulation. In pancreatic cancer, adipocytes activate the hypoxia signaling pathway, leading to increased expression of ANGPTL4 (134). This upregulation enhances β-oxidation in cancer cells and activates the STAT3 signaling pathway, promoting lipid metabolic reprogramming and metastasis of pancreatic cancer (134).

Amino acids, the building blocks of proteins, generate metabolites that fuel biosynthetic pathways, produce energy, and support cancer cell survival. Due to their heightened proliferative needs, cancer cells often cannot synthesize sufficient quantities of amino acids. The reprogramming of amino acid metabolism fulfills this increased demand (135).

Currently, limited research exists on the relationship between ANGPTL4 and the reprogramming of amino acid metabolism in cancer. Xiao et al (132) utilized tracer technology and Seahorse XF technology to explore the metabolic effects of ANGPTL4 in NSCLC. Their findings revealed that ANGPTL4 promotes glutamine consumption and fatty acid oxidation in NSCLC, both in vitro and in vivo, while having no significant effect on glycolysis. ANGPTL4 regulates glutaminase and CPT1, thereby facilitating glutamine metabolism and fatty acid oxidation, which in turn supports NSCLC cell proliferation (132). Lin et al (49) identified a negative correlation between ANGPTL4 and BCAA metabolism in OS samples and cell lines. The downregulation of ANGPTL4 in OS cells leads to the accumulation of BCAAs and the activation of mTOR signaling, which promotes OS cell proliferation (49).

Chemotherapy and radiotherapy are essential treatments for unresectable tumors and serve as neoadjuvant therapies. However, their clinical efficacy is often hindered by the development of resistance. Chemoresistance and radioresistance also contribute to tumor recurrence and metastasis, posing major challenges to patient prognosis (136,137). Research has increasingly focused on how ANGPTL4, a multifunctional molecule in tumor cell survival, proliferation and apoptosis, influences the resistance to chemotherapy and radiotherapy (Table III).

Chemoresistance promoted by ANGPTL4 is closely tied to its metabolic reprogramming functions. It has been shown that ANGPTL4 enhances cellular ATP through the c-Myc and NF-κ B signaling pathways during EMT (80). The increased ATP provides fuel for multiple ATP-binding cassette (ABC) transporters to upregulate their expression, ensuring sufficient cellular energy for drug efflux, thereby conferring chemoresistance in tumors (80). In HCC, ANGPTL4 induces the upregulation of pyruvate dehydrogenase kinase 4, an inhibitor of mitochondrial pyruvate dehydrogenase, enhancing the resistance to sorafenib and cisplatin in stem cells (138). These findings suggest that targeting the metabolic function of ANGPTL4 and combining the restoration of mitochondrial metabolic activity with chemotherapy present attractive therapeutic options in cancer treatment.

In OVC, TAZ has been shown to promote the resistance to cisplatin via the ANGPTL4/sex-determining region Y-box2 (SOX2) axis (139). Similarly, Zhou et al (140) reported that adipocyte-derived ANGPTL4 induces carboplatin resistance in OVC. ANGPTL4 activates the c-Myc/NF-κ B pathway, which subsequently stimulates the expression of the anti-apoptotic proteins and ABC transporter family members. However, Xu et al (102) came to the opposite conclusion. They found that TAZ activates the ANGPTL4/NOX2 axis, making OVC cells sensitive to ferroptosis and chemotherapy. TAZ levels were lower in chemotherapy-resistant recurrent OVC cells.

In GBM, where temozolomide (TMZ) combined with radiotherapy is the standard therapy, glioma stem-like cells (GSCs) are considered to be the primary cause of drug resistance. In the study of Tsai et al' (141), ANGPTL4 expression was significantly increased in GSCs. The overexpression of ANGPTL4 activates the PI3K/AKT, EGFR and ERK signaling pathways, enriching GSCs and resulting in TMZ resistance (141). Additionally, Gordon et al (142) showed that ANGPTL4 contributes to gemcitabine resistance in pancreatic cancer and shortens patient survival by regulating the expression of apolipoprotein L1 and integrin β4. In cholangiocarcinoma, Curcumin has been shown to enhance chemotherapy efficacy via the inhibition of ANGPTL4 (91). Furthermore, ANGPTL4 inhibits pyroptosis and apoptosis of lung adenocarcinoma cells through the NLRP3/ASC/Caspase-8 signaling pathway, contributing to the resistance against gefitinib (43).

The role of ANGPTL4 in radioresistance has also been recently explored. Hypoxia-induced ANGPTL4 expression has been positively correlated with radiotherapy resistance in NSCLC cells and xenograft tumors (101). ANGPTL4 promotes resistance through two mechanisms: intracellular ANGPTL4 and exosomal ANGPTL4. One pathway involves the upregulation of GPX4, which inhibits ferroptosis and lipid peroxidation (101).

The aforementioned studies suggest that ANGPTL4 could serve as a potential therapeutic target to enhance the efficacy of radiotherapy and chemotherapy. However, research on the relationship between ANGPTL4 and radioresistance remains limited, and further investigations are required to improve understanding of its effects, and underlying mechanisms in chemoresistance and radioresistance.