Nrf2, a Cap'n'collar/basic leucine zipper transcription factor that heterodimerizes with small Maf proteins, serve a crucial role in maintaining cellular redox homeostasis (34,35). Under physiological conditions, Kelch-like ECH-associated protein 1 (Keap1) serves as a cytoplasmic anchor for Nrf2, inhibiting HO-1 expression by forming a Keap1-Nrf2 complex (36,37). This complex facilitates Nrf2 recognition by Cullin 3-based E3 ubiquitin ligase, leading to Nrf2 ubiquitination and proteasomal degradation (38,39). However, upon exposure to oxidative stress, keap1 cysteine residues undergo modification, disrupting the Keap1-Nrf2 complex and promoting Nrf2 nuclear translocation (40). The antioxidant response element (ARE), also known as the Maf response or stress-responsive element, represents the primary cis-acting regulatory element within the promoter regions of target genes (41). Nrf2 binds to the ARE, activating the Nrf2/ARE signaling pathway. This pathway regulates transcription of downstream target genes, including HO-1 and NADPH quinone dehydrogenase 1 (NQO1), mitigating oxidative damage to cells and contributing to maintenance of redox homeostasis (25,42,43).

Nrf2 and Bach-1 bind to distinct sites within the promoter region of the HO-1 gene, with Bach-1 serving as a transcriptional repressor by competing with Nrf2 (44,45). Heme can directly inhibit Bach-1 DNA-binding activity, promote its nuclear export and inhibit Nrf2 proteasomal degradation, thereby upregulating HO-1 expression (46,47). The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is a key regulator of cell proliferation and apoptosis. Inactivating this pathway can downregulate Nrf2 levels, thereby inhibiting tumor cell proliferation, inducing apoptosis and enhancing tumor cell sensitivity to treatment (48). NF-κB also plays a key role in the development and progression of cancer (43). Under physiological conditions, IκB binds to NF-κB, forming an inactive complex that prevents NF-κB translocation from cytoplasm to the nucleus (48). Upon oxidative stress stimulation, NF-κB dissociates from IκB, initiating HO-1 transcription (43,49). Several other transcription factors are implicated in the cell type- and inducer-specific regulation of HO-1 transcription. These include activator protein-1 (AP-1), AP-2, heat shock factor-1, hypoxia-inducible factor-1, early growth response-1 protein and cyclic AMP response element-binding protein (50,51) (Fig. 1).

Both humans and mice express two isoforms of HO: HO-1, which is inducible, and HO-2, which is constitutively expressed in all cells (4,52). A third isoform, HO-3, lacking catalytic activity, has been identified in rats (53). HO-1 is a key player in the mammalian stress response (54,55) and was initially identified in early studies of microsomal metabolic processes as the rate-limiting enzyme in heme degradation (2,56). HO-1 catalyzes oxidative cleavage of heme at the α-methene bridge carbon, generating equimolar amounts of CO and BV while releasing Fe²⁺ (51). NAD(P)H: BV reductase then reduces BV to produce the lipid-soluble bile pigment bilirubin-IX (BR; Fig. 1) (57). CO exerts anti-apoptotic and anti-inflammatory effects by stimulating soluble guanylyl cyclase, increasing cGMP levels and MAPKs, which can synergize with other anti-apoptotic systems (43,58). CO is implicated in various physiological and pathological processes, including anti-proliferation (59). CO produced by increased HO-1 activity upregulates glutamate-cysteine ligase expression and restores glutathione (GSH) levels (60). BV and BR exhibit anti-apoptotic activity by promoting expression of anti-apoptotic protein Bcl-2 and suppressing the pro-apoptotic protein Bax (61). BR is a potent antioxidant in biological systems, capable of preventing excessive ROS from oxidizing lipids and proteins (62,63). The balance between iron and ROS levels influences HO-1 function. Excessive iron and ROS shift HO-1 from a cytoprotective role to a detrimental one, leading to DNA damage, genetic alteration and cell death (64). Therefore, precise control of HO-1 expression is key to maintain its cytoprotective effects. The pleiotropic effects of HO-1 may reflect a complex interplay between the production and distribution of bioactive catabolic products and their subsequent effects in contexts where HO-1 is associated with cytoprotection (54,65).

Biological and cellular functions of HO-1 may extend beyond catalytic heme breakdown, potentially involving unique subcellular compartmentalization and non-catalytic effector functions (66,67). HO-1 interacts with other proteins, including cytochrome P450, adiponectin and CD91, potentially serving as a protein chaperone (67). In the context of endothelial cell damage, an interaction between HO-1 and pro-apoptotic protein Bax has been identified, suggesting a potential anti-apoptotic mechanism (68). Studies in both non-malignant and tumor cells have shown that under stress conditions, HO-1 translocates to the nucleus (69,70). This requires proteolytic cleavage of its C-terminus within the smooth ER membrane, potentially mediated by SPP or other cysteine proteases, resulting in a truncated HO-1 form with decreased enzymatic activity (69,70). However, further investigation is necessary to determine whether pathogenic stimuli induce this proteolytic cleavage in a tumor setting (71). The truncated nuclear version of HO-1 (NHO-1) lacks heme-degrading activity (72). Current evidence suggests that NHO-1 serves as a regulator of nuclear transcription factor activities, including NF-κB, p65, AP-1 and Nrf2 (Fig. 1) (66). Bimolecular association of NHO-1 with Nrf2 stabilizes Nrf2 by preventing Glycogen synthase kinase-3-mediated phosphorylation and proteolytic degradation (72). Consequently, NHO-1 enhances transcriptional activity of Nrf2, leading to increased expression of numerous Nrf2 target genes, including NAD(P)H: quinone oxidoreductase 1 (NQO1) and glucose-6-phosphate dehydrogenase (72). In a model of blood-spinal cord barrier integrity, artificial overexpression of NHO-1 (COOH-terminal truncated version) confers protection (73). This protective effect is attributed to SOX5-mediated upregulation of tight junction protein expression and subsequent modulation of miR-181c-5p (73).

Evidence has accumulated indicating localization of HO-1 in subcellular compartments beyond the nucleus (74,75). Notably, while nuclear migration of HO-1 is associated with loss of enzymatic function, its migration from the smooth ER membrane to the mitochondria, vacuoles and plasma membrane appears to preserve this function (74). Mitochondrial localization of functionally active HO-1 has been documented under stress conditions, suggesting a potential role in regulating heme bioavailability for mitochondrial cytochromes (75). HO-1 has been shown to localize to plasma membrane caveolae and interact with caveolin-1, a scaffolding protein residing within these membrane invaginations (6,30,76). The interaction between caveolin-1 and HO-1 inhibits HO-1 activity, potentially serving as a regulatory mechanism for HO-1 function within this compartment (6,30). Although the functional role of these distinct subcellular localizations remains to be fully elucidated, it is possible that HO-1 serves as a localized source of CO generation, thereby contributing to specific signaling mechanisms within mitochondrial or caveolae compartments (75). The potential functions of a circulating, cell-free form of HO-1 in the extracellular environment have been proposed, such as suppressing organ transplantation rejection (67). While HO-1 levels fluctuate in various diseases and are detectable in both serum and cerebrospinal fluid, its functional role in extracellular fluids remains largely unknown (66).

The role of HO-1 has been demonstrated in various types of tumor (77). HO-1 expression exhibits a diverse pattern across different types of malignancy, with upregulation observed in some cancers and downregulations in others (Fig. 2A). HO-1 serves a pro-tumorigenic role in a majority of tumor types, including gastrointestinal cancer, glioma, head and neck, lung, thyroid and genitourinary cancer, melanoma and hematological malignancies (71). Conversely, an anti-tumorigenic role for HO-1 has been reported in certain malignancies, such as colon, hepatic, prostate, head and neck and lung cancer (71). HO-1 protein has been detected in extracellular vesicles derived from culture media of various cancer cell lines, including those originating from breast, lung and kidney cancer and melanoma (32). These findings suggest that HO-1 may exert tissue- and cell-specific roles in malignancy (78). Certain malignancies, such as renal cell carcinoma, melanoma and hepatoma, have been shown to exhibit both cytoplasmic and nuclear expression of HO-1 (78). Furthermore, evidence suggests subcellular localization of HO-1 can influence cancer cell behavior (79). The majority of studies investigating nuclear HO-1 in human cancer have focused on the association between localization and clinicopathological parameters, such as tumor grade, patient survival time and differentiation grade (78,80). These studies collectively indicate that HO-1 may serve dual and potentially opposing roles in cancer, depending on factors such as tumor type, HO-1 subcellular localization and threshold levels of HO-1 expression (81,82). Moreover, HO-1 expression is associated with CD4 (a marker of CD4⁺ T cells), CD163, V-set and immunoglobulin domain containing 4 and membrane spanning 4-domains A4A (markers of M2 macrophages), major histocompatibility complex, class II, DR beta 1 (HLA-DPB1), major histocompatibility complex, class II, DQ beta 1 (HLA-DQB1), major histocompatibility complex, class II, DR alpha (HLA-DRA), major histocompatibility complex, class II, DP alpha 1 (HLA-DPA1) and integrin subunit alpha X (ITGAX) (markers of dendritic cells), as well as C-C motif chemokine receptor 7 (CCR7) and integrin subunit alpha M (ITGAM) (markers of neutrophils) in pan-cancer analyses (Fig. 2B). HO-1 expression within infiltrating immune cells, including macrophages, dendritic cells, neutrophils, natural killer cells and T and B lymphocytes, can drive their polarization towards a tumor-promoting and immunosuppressive phenotype (32).

Apoptosis, also known as type I cell death, was the first form of PCD to be identified and was initially observed in Caenorhabditis elegans (91,92). A range of physiological and pathogen-induced events and conditions can trigger apoptosis. Typically, it is initiated through either an intrinsic (mitochondrial) or extrinsic (death receptor-mediated) pathway (93). Both intrinsic and extrinsic apoptotic pathways converge on the activation of effector caspases-3 and −7 at the end of the caspase cascade (94). The activation of caspases-3 and −7 leads to characteristic morphological features of apoptosis, including membrane blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation and the exposure of phosphatidylserine on the cell surface. These events culminate in formation of small, intact-appearing vesicles (apoptotic bodies), which are rapidly engulfed by neighboring cells through phagocytosis (92). Previous research has established the crucial role of apoptosis in the elimination of malignant cells (95). However, the specific function of HO-1 in apoptosis remains to be fully elucidated. Studies on drug-induced apoptosis in tumor cells have reported both up- and downregulation of HO-1 expression, suggesting a complex and potentially context-dependent role for this enzyme in the apoptotic process (96,97).

Magnolol (5,5′-diallyl-2,2′-dihydroxybiphenyl), isolated from the traditional Chinese medicinal herb Magnolia officinalis, induces caspase-mediated apoptotic cell death in human oral cancer cells through the JNK1/2 and p38 MAPK pathways, accompanied by upregulation of HO-1 (98). Chrysosplenol D, a flavonol isolated from Artemisia annua L., triggers apoptosis through HO-1 activation and MAPK signaling in oral squamous cell carcinoma (99). Picrasidine I (from Picrasma quassioides) causes HO-1-mediated apoptosis in nasopharyngeal cancer cells by inhibiting ERK and Akt signaling pathways (100). Gambogic acid induces HO-1 expression and triggers apoptosis via p38 signaling in oral squamous cell carcinoma (101). Curcumin and 3′,4′-didemethylnobiletin demonstrate synergistic anticancer effects on colon cancer cells, accompanied by increased HO-1 levels (102). Crocin, a water-soluble dicarboxylic acid monoglyceride (carotenoid) derived from saffron, exerts a chemopreventive effect against experimentally induced hepatocarcinogenesis via regulation of apoptotic pathways and the Keap1/Nrf2/HO-1 signaling pathway (103). Deoxyshikonin, a phytochemical constituent of the roots of purple cromwell, induces an apoptotic response in tongue cancer cell lines by activating the Nrf2/HO-1 signaling axis (104). In vitro and in vivo studies have demonstrated that indolyl-chalcone derivative 3d induces apoptosis and activates the Nrf2/HO-1 pathway, suppressing the proliferation of A549 lung cancer cells (105,106). Dual targeting of the p38/MAPK/HO-1 axis and cellular inhibitor of apoptosis protein 1/X-linked inhibitor of apoptosis protein by demethoxycurcumin (derived from rhizomes of curcuma longa linn) triggers caspase-mediated apoptotic cell death in oral squamous cell carcinoma cells (107). (2E,2′E)-1,1′-(cyclohexane-1,1-diyl)bis[3-(3,4-dimethoxyphenyl)prop-2-en-1-one], a synthetic analog of curcumina, triggers caspase-mediated apoptotic cell death in human oral cancer cells by activating the p38/HO-1 pathway (108). In HT-29 colorectal cancer cells, copper imidazo(1,2-a) pyridines boost expression of the HO-1/HMOX/heatshock protein 32 pathway-associated proteins, leading to the accumulation of ROS and induction of intrinsic apoptosis (109).

Protocatechuic acid, a plant-derived secondary metabolite, induces apoptosis in colon cancer cells by promoting oxidative stress via downregulation of HO-1 and upregulation of p21 (110). Numerous synthetically derived chemotherapeutic agents exert anti-tumor effects by inducing apoptosis, often via modulation of HO-1 expression. TW37, a small-molecule inhibitor of Bcl-2 family proteins, decreases HO-1 expression, thereby mediating anti-proliferative and pro-apoptotic effects in human oral tongue YD-15 cells (111). LMK-235, a selective inhibitor of histone deacetylase 4/5 (HDAC4/5), induces apoptosis in B cell acute lymphoblastic leukemia (B-ALL) and multiple myeloma cells via downregulation of HO-1 expression (112,113). Lotus leaf flavonoids induce apoptosis in human lung cancer A549 cells by increasing ROS and malondialdehyde levels, accompanied by downregulation of Nrf2/HO-1 pathway signaling (114). Banxia Xiexin decoction, a traditional Chinese herbal formula, alleviates colon cancer in nude mice by downregulating Nrf2/HO-1 pathway signaling (115). Apatinib, a tyrosine kinase inhibitor, decreases Nrf2/HO-1pathway activity and reduced GSH levels, leading to ROS accumulation and apoptosis in ovarian cancer cells (116). Puerarin, the principal bioactive ingredient from the traditional Chinese herb Radix puerariae, inhibits the Keap1/Nrf2/HO-1/NQO1 signaling pathway, thereby inducing apoptosis in prostate cancer cells (117). The combination of cyanidin-3-O-glucoside and cisplatin induces oxidative stress and apoptosis in HeLa cells via the downregulation of Nrf2/HO-1/NQO1 expression (118). In combination with trastuzumab, brusatol, an Nrf2 inhibitor, suppresses the human epidermal growth factor receptor 2 (HER2/AKT/ERK1/2 and Nrf2/HO-1 pathways, exerting an ant-cancer effect on HER2-positive tumors (119). Extracts of Murraya koenigii target the PI3K/AKT/Nrf2/HO-1/caspase-3 signaling pathway in human non-small cell lung cancer (NSCLC), specifically inducing apoptosis (120). Furthermore, the Pim proto-oncogene, serine/threonine kinase inhibitor 5-[(3-(trifluoromethyl)phenyl]methylidene]-1,3-thiazolidine-2,4-dione) induces apoptosis in B-ALL cells via the HO-1-mediated JAK2/STAT3 pathway (121). In chronic lymphocytic leukemia, characterized by TP53 mutations, combined administration of entinostat and fludarabine induces apoptosis through inhibition of the HDAC1/p38/HO-1 pathway (122). Gambogic acid, a natural compound isolated from gamboge (a dry resin secreted from Garcinia hanburyi tree in Southeast Asia) synergistically potentiates cisplatin-induced apoptosis in NSCLC by suppressing NF-κB and MAPK/HO-1 signaling pathways (123) (Table I).

Ferroptosis is a distinct form of iron-dependent necrotic cell death associated with propagation of inflammation (124). This form of cell death is characterized by severe lipid peroxidation, mitochondrial shrinkage and increased mitochondrial membrane density (125). Inhibition of cysteine uptake is a primary inducer of ferroptosis. This leads to impaired synthesis of reduced GSH, which serves as a substrate for GSH peroxidase-4 (GPX4)-mediated detoxification of lipid hydroperoxides (126). Under cysteine deprivation, ferritin breakdown is facilitated by nuclear receptor coactivator 4-mediated selective autophagy (127). While numerous reports describe HO-1 expression as either promoting or inhibiting ferroptosis, the precise role of HO-1 in this process remains elusive (128,129). While HO-1 may exert a protective effect by in mitigating pro-oxidant states and preserving mitochondrial function, which are implicated in the initiation of inflammatory cell death and apoptosis, HO-1 also releases iron as a reaction byproduct (130,131). Excess or unabsorbed ferrous iron is involved in the initiation of ferroptosis. Therefore, the role of HO-1 in ferroptosis is context-dependent (132).

Extracts from Betula etnensis Raf. (Betulaceae) stimulate an oxidative cellular milieu, inducing ferroptosis in CaCo2 cells through HO-1 upregulation (133). EF24, a synthetic analog of curcumin, induces ferroptosis in osteosarcoma cell lines by elevating ROS and intracellular ferric ion concentrations, leading to activation of HO-1 and suppression of GPX4 expression (134). In breast cancer cells, ferroptosis is induced by high HO-1 expression following treatment with curcumin (135). Luteolin, a naturally occurring flavonoid widely distributed in fruits and vegetables, upregulates HO-1 expression, increased the labile iron pool, and promotes lipid peroxidation, thereby triggering ferroptosis in clear renal cell carcinoma (136). Eupalinolide B (derived from Eupatorium) induces ferroptosis in hepatocellular carcinoma cells by activating HO-1 (137). Honokiol, a biphenolic phytochemical derived from Magnolia species, induces ferroptosis by upregulating HO-1 in acute myeloid leukemia cells (138). Cefotaxime sodium demonstrates highly specific and selective anticancer activity in nasopharyngeal carcinoma CNE2 cells by overexpressing HO-1 and triggering ferroptosis (139). Arsenic trioxide enhances ferroptosis of SK-N-BE neuroblastoma cells, partially via induction of HO-1 expression (140). KRAS-mutant colorectal cancer cells with HO-1 overexpression undergo ferroptosis following treatment with a combination of β-elemene and cetuximab (141). Shuganning injection, a traditional Chinese medicine, induces ferroptosis and suppresses tumor growth in triple-negative breast cancer cells in a HO-1 dependent manner (142). Sophora alopecuroide-Taraxacum decoction, a herbal medicine utilized in China, enhances ferroptosis in NSCLC by elevating expression of HO-1 (143). One of the key mechanisms underlying ferroptosis induction is the Nrf2/HO-1 axis. Tagitinin C, a sesquiterpene lactone derived from Tithonia diversifolia, activates the pseudopodium enriched atypical kinase 1/Nrf2/HO-1 signaling pathway, leading to ferroptosis in colorectal cancer cells (144). Cyclophosphamide induces ferroptosis in glioblastoma and murine breast cancer cells through the activation of the Nrf2/HO-1 pathway (145). Similarly, di-2-pyridylhydrazone dithiocarbamate butyric acid ester (DpdtbA) promotes activation of the Keap1/Nrf2/HO-1 pathway in gastric cancer cell lines, resulting in the induction of ferroptosis (146).

Siramesine, a lysosomal destabilizing drug, and lapatinib, a dual tyrosine kinase inhibitor, synergistically induce ferroptosis by decreasing HO-1 expression and elevating iron release from lysosomes (147). Dihydroartemisinin (derived from sweet wormwood) enhances the inhibitory effect of sorafenib on HepG2 cells by decreasing HO-1 expression, inducing ferroptosis and inhibiting energy metabolism (148). Ginkgetin, derived from Ginkgo biloba leaves, triggers ferroptosis in NSCLC cells by disrupting the Nrf2/HO-1 pathway (149). Similarly, neferine (derived from lotus) inhibits the Nrf2/HO-1/NQO1 pathway, inducing ferroptosis and exerting anticancer effects on thyroid cancer (150). S-3′-hydroxy-7′,2′,4′-trimethoxyisoxane, a novel ferroptosis inducer, enhances NSCLC cell death by blocking the Nrf2/HO-1 signaling pathway (151). Both carboxymethylated pachyman and norcantharidin induce ferroptotic death in ovarian cancer cells by suppressing the Nrf2/HO-1/xCT/GPX4 axis (152,153). Induction of ferroptosis by carnosic acid-mediated inactivation of the Nrf2/HO-1 pathway potentiates cisplatin responsiveness in human oral squamous cell carcinoma cells (154) (Table II).

Autophagy, a pivotal proteolytic mechanism that delivers cytoplasmic constituents to the lysosome for degradation by hydrolytic enzymes, serves a key role in cellular energy mobilization and homeostasis by removing pathogens, aggregated proteins and damaged organelles (169). This system is activated by stressors, including nutrient or energy deprivation, oxidative stress, hypoxia, mitochondrial dysfunction and pathogen infection (170). Autophagy dysfunction contributes to pathogenesis of numerous diseases, including cancer, diabetes and neurodegenerative disorder (171). Autophagy plays a critical role in tumor growth and drug resistance by assisting tumor cells in coping with intracellular and environmental stress and surviving oxidative processes (172). Conversely, uncontrolled autophagy may inhibit tumor growth and autophagy activators could represent a promising therapeutic strategy (173). P62 and LC3 are commonly used as markers of autophagic activity (174–176).

AT 101 [(−)-gossypol], a natural compound derived from cottonseed, induces autophagic cell death in glioma cells primarily via early mitochondrial dysfunction and HO-1 overactivation (177). Increased HO-1 activity is also observed in cadmium-treated squamous epithelium YD8 cells, along with increased ROS production and decreased catalase and superoxide dismutase 1/2 expression, resulting in increased autophagy (178). Sinoporphyrin sodium, a photosensitizer isolated from photofrin, induces autophagy in human esophageal cancer Eca-109 cells, with ROS generation and HO-1 activation following photodynamic therapy (179). Isodeoxyelephantopin (derived from Elephantopus scaber L.) induces protective autophagy in lung cancer cells via activating the Nrf2/HO-1/p62/Keap1 feedback loop (180). The induction of HO-1 by the Src/STAT3 axis protects MDA-MB-231 breast cancer cells from doxorubicin-induced death by promoting autophagy (181). Apatinib, a tyrosine kinase inhibitor, promotes ROS-dependent autophagy by downregulating the Nrf2/HO-1 pathway in ovarian cancer cells (116) (Table III).

Necroptosis, a genetically regulated form of necrotic cell death, is increasingly recognized as a key contributor to human diseases (182,183). Necroptosis exhibits numerous morphological features characteristic of accidental necrosis, such as organelle swelling, plasma membrane rupture, cell lysis and the release of intracellular components. These events trigger secondary inflammatory responses via release of damage-associated molecular patterns (184). Consequently, necroptosis, similarly to unregulated necrosis, constitutes an inflammatory mode of cell death. The necroptosis pathway is activated by signals, including stimulation of cells with death-receptor ligands. Necroptosis is regulated by receptor-interacting protein kinase (RIPK)-1 and −3 and MLKL, which oligomerize to form a regulatory ‘necrosome’ complex in the canonical pathway (185). A key event in necroptosis activation is phosphorylation of MLKL by RIPK3 (186). To the best of our knowledge, only a limited number of pharmacological studies have investigated the association between HO-1 and necroptosis in cellular and animal models of femoral head necrosis and neurodegenerative diseases (187,188). Benzo[a]pyrene exposure notably induces necroptosis in long bone-derived osteocyte-like MLO-Y4 cells by downregulating Nrf2/HO-1 expression, leading to oxidative damage (187). ROS scavenger N-acetylcysteine inhibits necroptotic death (187). Selumetinib, a mitogen-activated protein kinase kinase (MEK)-extracellular regulated protein kinases (ERK) inhibitor, prevents necroptosis by suppressing the activity of caspase 3, RIP1, RIP3 and the Nrf2/HO-1 axis in rats (188) (Table III).

In 1829, Jean Claude first described ‘metastasis’ as a characteristic of cancer, highlighting it as a crucial therapeutic target in cancer research (196). Metastasis, a complex series of events involving dissemination of tumor cells from the primary site to distant organs to form secondary tumors, is responsible for ~90% of cancer-related deaths (197,198). Directed migration is underpinned by four key processes: Signal generation, detection, transmission and execution (199). Epithelial-mesenchymal transition (EMT) involves loss of cell-cell and cell-extracellular matrix adhesion in epithelial cells, leading to acquisition of a mesenchymal phenotype. This facilitates the detachment of cells from the primary site and surrounding tissue, enabling their dissemination to distant organs. The RAS/RAF/MEK/ERK signaling pathway has been shown to promote cell motility in various types of malignancy, such as prostatic carcinoma and melanoma (200,201). Furthermore, growing evidence suggests that numerous members of the microtubule-associated protein family may function as critical regulators, modulating microtubule dynamics and promoting the migration and invasion of cancer cells (202,203). However, the role of HO-1 in the context of metastasis remains controversial and may be influenced by factors that are not yet fully understood (204,205). Ferulic acid, a phenolic compound, inhibits growth and invasion of esophageal squamous cell carcinoma tumors by enhancing HO-1 activity and inducing ferroptosis (206). Combined treatment with β-elemene and cetuximab suppresses EMT in KRAS-mutant colorectal cancer cells by upregulating HO-1 and inducing ferroptosis (141). Saxagliptin, a dipeptidyl peptidase-IV inhibitor used to manage blood glucose levels in patients with type 2 diabetes, facilitates migration and invasion of thyroid carcinoma cells. This effect is associated with increased expression of MMP2 and VEGF, primarily driven by activation of the NRF2/HO-1 pathway (207). A recent study demonstrated that DpdtbA suppresses EMT in gastric cancer cell lines (SGC-7901 and MGC-823) by activating the Keap1/Nrf2/HO-1 pathway (146). Qingyihuaji formula, a traditional Chinese medicine, suppresses the invasion and migration of pancreatic cancer via activation of the Nrf2/HO-1/NQO1 axis (208). Pygenic acid A, a natural compound derived from Prunella vulgaris, sensitizes metastatic breast cancer cells to anoikis and inhibits metastasis in vivo by downregulating the expression of p21, cyclin D1, phosphorylated STAT3 and HO-1 (209). Danthron (derived from rhubarb) inhibits proliferation and migration of HeLa cells by interfering with the interaction between HO-1 and cytochrome P450 reductase (210). 15-Deoxy-D12,14-prostaglandin J2, a natural ligand of peroxisome proliferator-activated receptor g (PPARg), suppresses the PPARγ/HO-1 signaling pathway and inhibits the invasion of breast cancer cells (211) (Table IV).

Oxidative stress is a physiological state characterized by an imbalance between pro-oxidants, such as ROS, and antioxidants (212). Excessive generation and accumulation of ROS damage cellular macromolecules and tissues, contributing to the pathogenesis of diseases, including cancer, inflammation and diabetes (213). In response to oxidative stress, cells activate defense mechanisms involving both enzymatic and non-enzymatic antioxidants. Key enzymatic antioxidants include GPX, superoxide dismutase and catalase. GSH is considered the most crucial component of non-enzymatic antioxidant defense (214). The Nrf2-HO-1 axis, a redox-sensitive signaling pathway, regulates expression of genes involved in antioxidant defense and detoxification (215).

Larval extracts from the oriental hornet (Vespa orientalis) induce antioxidant effects in MCF7 cells by activating the Nrf2/HO-1 pathway (216). Trehalose, a non-reducing disaccharide composed of two D-glucose units linked by an α-1,1 glycosidic bond, protects against oxidative stress by upregulating p62/Keap1/Nrf2/HO-1 signaling in human hepatocellular carcinoma cells (217). Curcumin exerts anti-oxidative activity in human neuroblastoma cells by inducing the activation of the Nrf2/HO-1 pathway (218). (3R,4S)-3,4-bis(4-hydroxyphenyl)-8-methyl-3,4-dihydro-2H-chromen-7-ol (ME-344) is a second-generation isoflavone related to phenoxodiol that has promise as an anticancer agent (219). By directly targeting HO-1 protein, ME-344 disrupts mitochondrial translocation in human lung cancer cells, thereby disrupting redox homeostasis and mitochondrial function (219). Cordycepin (3′-deoxyadenosine), a bioactive compound extracted from Ophiocordycipitaceae fungi, inhibits Nrf2/HO-1 signaling both in vitro and in vivo, leading to increased ROS levels in breast cancer cells (220). Galangin, a flavonoid isolated from the rhizome of Alpinia officinarum (Hance), inhibits gastric cancer cell proliferation by increasing ROS accumulation, downregulating Nrf2 and simultaneously upregulating HO-1 (221) (Table IV).

TIME is characterized by various factors that contribute to tumor development, progression and proliferation, such as cytokines and immune cells (222). These factors limit supply of essential nutrients and oxygen, hinder effective immune surveillance and obstruct the delivery of therapeutic agents (222,223). Advancements in tumor immunotherapy strategies are associated with deeper understanding of TIME. Within this environment, both malignant tumor and stromal cells have been identified as expressing HO-1, a key enzyme in the regulation of cellular processes (78,224). HO-1 upregulation in tumor-associated macrophages has been shown to facilitate tumor progression and enhance the immune suppressive characteristics of the TIME (78,224). The catabolites produced by HO-1, including CO, modulate the phenotype, activation state and cytokine profiles of various stromal cell populations (225). This modulation contributes to the ability to evade immune detection and response (226). Tumor-associated macrophages constitute the predominant stromal cell type within the TIME and are the primary source of HO-1 in both murine ovarian carcinoma model and human cancer (227,228). In addition to macrophages, other immune cells present in the TIME, such as dendritic cells and T cell subsets (CD4⁺, CD8⁺ and Foxp3⁺ regulatory T cells), exhibit HO-1 expression. The presence of HO-1 in these immune cells may alter their functional capacity and decrease their ability to elicit an immunogenic response (198,229). Moreover, catabolites of heme degradation have the potential to diffuse into the extracellular matrix, thereby impacting neighboring immune cells that do not express HO-1. This can influence the polarization and recruitment of various immune cells, highlighting the importance of HO-1 in orchestrating the immune landscape within the TIME (227). These findings underscore the therapeutic potential of targeting HO-1 as part of an immunotherapy strategy. Several existing drugs demonstrate anti-tumor effects by specifically targeting HO-1 in immune cells. For example, inhibition of HO-1 is associated with enhanced immunotherapeutic effect on tumor growth (227). Cucurbitacin I, for example, downregulates HO-1, resulting in a notable decrease in the M2-like polarization phenotype of macrophages (230). Among inhibitors of HO-1, Zinc Protoporphyrin is most effective in counteracting the immune suppression caused by bone marrow-derived macrophages derived from human glioblastoma tissue samples, thereby promoting anti-tumor effects (231).