From mechanism to clinic: a panoramic perspective on targeting HMOX1 to overcome drug resistance.

Introduction
Malignant tumors represent a major public health threat to humanity. In 2022, there were approximately 19.7 million new cancer cases and 9.7 million cancer-related deaths worldwide (Bray et al. 2024). Despite breakthroughs in chemotherapy, targeted therapy, and immunotherapy that have significantly improved patient survival, drug resistance remains the primary cause of disease progression, recurrence, and ultimate treatment failure (Vasan et al. 2019).
Chemotherapy, a cornerstone of cancer treatment, utilizes one or more anticancer agents in standardized regimens. Its major limitations, however, are the lack of selectivity of cytotoxic drugs between tumor and normal cells, and the development of resistance to specific or multiple drugs by tumor cells (Engle and Kumar 2022). Although renowned for its precision, targeted therapy is invariably followed by acquired resistance, often via mechanisms such as target gene mutations (Aldea et al. 2021; Song et al. 2025). Similarly, immunotherapies, including immune checkpoint inhibitors (ICIs), despite their remarkable efficacy in certain cancers, are constrained by primary or acquired resistance (Pang et al. 2023; Vesely et al. 2022). The emergence of drug resistance not only severely compromises therapeutic efficacy but also exacerbates the physical and financial burdens on patients.
The mechanisms underlying drug resistance are complex and multifaceted, primarily encompassing the following aspects. (1) Enhanced Drug Efflux: Tumor cells overexpress ATP-binding cassette (ABC) transporter family proteins, such as P-glycoprotein, on their surface. These proteins actively pump drugs out of the cell, thereby reducing intracellular drug concentration (Guo et al. 2024; Wang et al. 2023). (2) Augmented DNA Damage Repair: Mutations in DNA damage repair genes, including those involved in homologous recombination repair and mismatch repair, enable the efficient repair of therapy-induced DNA lesions, allowing cells to evade apoptosis (Liu et al. 2023; Wei et al. 2023). (3) Inhibition of Cell Death: Apoptosis and autophagy are key regulatory events in cell death. Alterations in the levels of apoptotic and anti-apoptotic proteins, coupled with autophagy providing nutrients to cancer cells, lead to the suppression of cell death (Ajmeera and Ajumeera 2024; Shen et al. 2024). (4) Alterations in the Tumor Microenvironment (TME): Surrounding components, such as immune cells and the extracellular matrix, can compromise therapeutic efficacy by suppressing anti-tumor immune responses (Lamplugh et al. 2025; Liu et al. 2024a, b, c, d). (5) Epigenetic Mechanisms: Cancer cells utilize epigenetic alterations, particularly histone modifications and DNA methylation, to activate oncogenes or inactivate tumor suppressor genes. This leads to dysregulated signaling pathways and contributes to the development of drug resistance (Yamagishi et al. 2024).
In the quest for novel strategies to overcome drug resistance, HMOX1 has emerged as a significant focus of research. HMOX1 is the rate-limiting enzyme that catalyzes the degradation of heme into CO, Fe²+, and biliverdin, which is subsequently reduced to bilirubin (Canesin et al. 2021). This process releases iron ions, promoting iron accumulation and inducing ferroptosis (Wei et al. 2021).
The function of HMOX1 is a “double-edged sword”. Its catabolic products exert anti-inflammatory and antioxidant effects, mitigating oxidative stress and providing cytoprotective effects, which can contribute to drug resistance in tumor cells (O’Rourke et al. 2024). Conversely, the overexpression of HMOX1 can also promote the generation of reactive oxygen species (ROS) and the accumulation of iron, thereby triggering iron-dependent lipid peroxidation and ultimately activating ferroptosis (Zhu et al. 2025). This dual role positions HMOX1 as a therapeutic target that requires precise modulation.
This review aims to systematically elucidate the core molecular mechanisms of HMOX1 in drug resistance, provide a panoramic perspective on strategies for targeting HMOX1, and delve into the challenges and future directions for its translation from basic research to clinical application. The goal is to establish a theoretical foundation for developing novel HMOX1-based strategies to reverse drug resistance.

Mechanisms of HMOX1 in drug resistance

Regulatory network of HMOX1

Transcriptional regulation
The Kelch-like ECH-associated protein 1 (Keap1) /NF-E2-related factor 2 (Nrf2) pathway is the primary regulator of HMOX1 expression (Li et al. 2021a, b). Under basal conditions, the transcription factor Nrf2 is recognized by Keap1 in the cytoplasm and targeted for degradation via the ubiquitin-proteasome pathway. Upon elevated oxidative stress, critical cysteine residues of Keap1 are modified, resulting in inhibition of Keap1-mediated Nrf2 degradation. Consequently, newly synthesized Nrf2 accumulates in the cytoplasm, escapes Keap1-mediated turnover, translocates into the nucleus, and binds to antioxidant response elements (ARE) to activate target genes including HMOX1 (Liu et al. 2024a, b, c, d; Lu et al. 2023; Yang et al. 2022). In various cancers, constitutive activation of Nrf2 is a key mechanism leading to high HMOX1 expression and subsequent mediation of chemoresistance (Mei et al. 2025).
BTB and CNC homology 1 (Bach1) is a transcription factor that binds to ARE and competitively inhibits Nrf2 (Bathish et al. 2022). As a heme-binding transcription factor, Bach1 enhances oxidative stress by downregulating HMOX1 expression (Yao et al. 2023; Yuan et al. 2024). When heme levels are elevated, Bach1 is degraded, a process that induces HMOX1 expression and promotes heme catabolism (Liu et al. 2024a, b, c, d).
Hypoxia-inducible factor-1α (HIF-1α) is a key regulator of cellular adaptation to hypoxia (Cowman and Koh 2022). The hypoxic microenvironment, resulting from malignant tumor growth, leads to increased HIF-1α protein expression and enhanced drug resistance (Méndez-Blanco et al. 2018). The transcription of HMOX1 is controlled by HIF-1α, and its upregulation can increase HMOX1 expression, thereby promoting ferroptosis (Lu et al. 2024).
Activator protein-1 (AP-1), a heterodimer or homodimer of proteins from the c-Jun and c-Fos families, is an important transcription factor involved in anti-inflammatory responses (Cantoni et al. 2003). The dysregulation of AP-1 is associated with cancer initiation, progression, invasion, metastasis, and drug resistance (Song et al. 2023). Upon activation, the AP-1 complex translocates to the nucleus and specifically binds to the promoter region of the HMOX1 gene. Multiple AP-1 binding sites are present on the HMOX1 promoter (Alam and Den 1992; Lavrovsky et al. 1994).
Nuclear Factor-kappa B (NF-κB) is a crucial transcriptional activator of HMOX1. Upon pro-inflammatory stimulation, NF-κB subunits translocate into the nucleus and bind to specific consensus sequences within the HMOX1 promoter. This binding initiates the transcription of HMOX1, thereby playing a pivotal role in cytoprotection and neutralizing oxidative stress (Medina et al. 2020). Concurrently, HMOX1 and its products can reciprocally inhibit the activity of NF-κB, forming a protective negative feedback regulatory mechanism (Chudy et al. 2025).
Heat shock factor 1 (HSF1) is the primary transcriptional activator of the HMOX1 gene under proteotoxic stress. Upon activation, HSF1 trimers bind to the Heat shock elements (HSE) within the HMOX1 promoter region, significantly upregulating its mRNA levels (Alam and Cook 2007).

Epigenetic regulation
The Ten-eleven translocation (TET) family of proteins plays a central role in regulating DNA methylation. In drug-resistant cells, the upregulation of TET1 mediates the demethylation of the Nrf2 promoter region, leading to Nrf2 activation and subsequent induction of HMOX1 (Kang et al. 2014). Histone modification promotes the transcriptional activation of Nrf2, which in turn upregulates the expression of its target gene, HMOX1. The HMOX1 protein then alleviates the toxicity of 5-Fluorouracil to cancer cells by eliminating ROS (Kang et al. 2016).

Post-transcriptional regulation
Certain microRNAs (miRNAs) participate in various cellular processes by mediating the degradation or translational inhibition of their target mRNAs (Ferragut Cardoso et al. 2021). For example, miR-141 can target Keap1, leading to Nrf2 nuclear translocation, activation of the Nrf2 pathway, and upregulation of HMOX1 expression. This results in elevated HMOX1 protein levels and promotes the formation of a drug-resistant phenotype (Shi et al. 2015). In contrast, miR-29b-3p enhances the sensitivity of non-small cell lung cancer (NSCLC) cells to cisplatin by targeting vascular endothelial growth factor (VEGF) to regulate the Nrf2/HMOX1 signaling pathway (Sun et al. 2024).

Regulation by post-translational modifications
Post-translational modifications (PTM) play pivotal roles in cellular biological processes, including phosphorylation, acetylation, glycosylation, and ubiquitination (Pan and Chen 2022). Among these, ubiquitination primarily determines the stability of HMOX1; inhibition of HMOX1 ubiquitination leads to its excessive accumulation within tumor cells, thereby inducing tumor cell death or promoting tumor cell migration and invasion (Gao et al. 2024; Lin et al. 2013). However, current research directly addressing the phosphorylation or acetylation of HMOX1 itself is very limited.

HMOX1-mediated pro-survival and anti-apoptotic mechanisms

Counteracting oxidative stress
Oxidative stress, characterized by the production of intracellular ROS, plays a key role in cancer development. Elevated ROS levels disrupt cellular homeostasis, leading to the loss of normal cellular functions, which is associated with the initiation and progression of various cancers (Iqbal et al. 2024). One of the primary mechanisms of chemotherapy and radiotherapy is to generate ROS to kill tumor cells (Guo et al. 2025). Tumor cells can counteract high ROS levels under oxidative stress by enhancing the synthesis of antioxidants or the expression of antioxidant enzymes, which makes them resistant to ROS-associated chemotherapy (Liang et al. 2025). HMOX1 catalyzes the production of biliverdin from heme, which is then converted by biliverdin reductase A into bilirubin. Acting as an endogenous antioxidant, bilirubin scavenges ROS, thereby protecting tumor cells(Mancuso 2025). CO, produced from heme catabolism by HMOX1, acts as an antioxidant and anti-apoptotic molecule that can reduce the sensitivity to chemotherapy and radiotherapy. However, HMOX1 plays a dual role in drug resistance, as it can also reverse resistance through various mechanisms (Cui et al. 2022; Tien Vo et al. 2021).

Inhibition of apoptosis
The anti-apoptotic effect of HMOX1 is closely related to CO. Acting as an anti-apoptotic molecule, CO inhibits apoptosis through the p38 mitogen-activated protein kinases (MAPK)-signal transducer and activator of transcription (STAT) or protein kinase B (Akt/PKB)-STAT pathways (Kim et al. 2006). The activation of HMOX1 regulates anti-apoptotic processes in gastric cancer cells through p38 MAPK and extracellular regulated protein kinases (ERK) mediated pathways (Jain et al. 2025). In renal cell carcinoma, activation of the oncogenic Ras-Raf-ERK signaling pathway induces HMOX1 overexpression, which promotes cancer cell survival by inhibiting apoptosis (Banerjee et al. 2011). Paradoxically, in multiple experiments using chemical carriers to deliver exogenous CO, CO has been shown to induce cancer cell apoptosis and inhibit cancer cell proliferation (Tien Vo et al. 2021).

Promotion of angiogenesis
CO promotes the proliferation of endothelial cells and angiogenesis (Chillà et al. 2025; Gomes Araujo et al. 2025). This pro-angiogenic effect is also central to tumor biology. The hypoxic tumor microenvironment prolongs the activity of HIF-1α and induces the expression of HMOX1 and VEGF, thereby promoting angiogenesis and malignant tumor growth (Cheng et al. 2016). Furthermore, the overexpression of HMOX1 can also induce VEGF synthesis (Dulak et al. 2008). Notably, due to its dual role, CO also exerts an anti-angiogenic effect in tumor cells, inhibiting the proliferation of drug-resistant cancer cells. The same effect has also been observed in mouse models (Cui et al. 2022).

Regulatory role of HMOX1 in ferroptosis
Ferroptosis is a form of iron-dependent, lipid peroxidation-driven cell death that was first proposed in 2012 (Dixon et al. 2012; Hangauer et al. 2017), and its role in cancer has been gaining increasing attention. Due to their unique metabolic characteristics, drug-resistant cancer cells are more sensitive to ferroptosis (Hangauer et al. 2017). HMOX1 serves as a significant source of intracellular labile iron. When HMOX1 activity is excessive or constitutively active, it generates an abundance of free iron. These iron ions catalyze the production of copious lipid-derived ROS through the Fenton reaction, leading to the rapid accumulation of lipid peroxides and triggering ferroptosis (Zeng et al. 2023). As mentioned previously, the HMOX1 metabolites biliverdin and carbon monoxide possess antioxidant properties. However, reports regarding the upregulation of HMOX1 inhibiting ferroptosis are relatively rare (Cheng et al. 2025; Zuo et al. 2025). We hypothesize that when HMOX1 activation is moderate and cellular iron-handling capacity is sufficient, the antioxidant effects of bilirubin predominate, potentially inhibiting ferroptosis. In contrast, excessive HMOX1 activation increases iron ions, leading to ROS overload that exceeds the cellular clearance capacity, thereby promoting ferroptosis. Thus, ROS levels and the degree of oxidative damage are critical factors in HMOX1-mediated regulation of ferroptosis (Chiang et al. 2018).

Remodeling of the tumor microenvironment by HMOX1
The tumor microenvironment comprises immune cells, cancer-associated fibroblasts (CAFs), and the extracellular matrix, among other components (Altorki et al. 2019). Among these, tumor-associated macrophages (TAMs) are an integral part of the tumor microenvironment. They enable tumors to escape immune surveillance by releasing immunosuppressive cytokines [such as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β)], expressing immune checkpoint molecules [like programmed death-ligand 1 (PD-L1)], or recruiting other immunosuppressive cells [including regulatory T cells (Tregs)] (Magri et al. 2022). Undifferentiated macrophages can polarize into pro-inflammatory and anti-tumor M1 macrophages when stimulated by factors such as interferon-γ (IFN-γ) and lipopolysaccharide. Conversely, IL-4 and IL-13 drive macrophage polarization toward the M2 phenotype, which possesses anti-inflammatory and tumor-promoting properties (Liang et al. 2025). M2 macrophocytes contribute to drug resistance by creating an immunosuppressive microenvironment and promoting angiogenesis (Li et al. 2023).
In tumor types characterized by immunosuppression (such as glioblastoma), HMOX1 is highly expressed in bone marrow-derived macrophages, fostering immunosuppression by influencing IL-10 release and PD-L1 expression (Magri et al. 2022). Du et al. reported that in the hepatocellular carcinoma microenvironment, HMOX1+ macrophages recruit Tregs via the CXC chemokine motif ligand 12 (CXCL12)-CXC chemokine receptor 4 (CXCR4) signaling axis and exhibit an immunosuppressive status. Notably, the HMOX1 inhibitor zinc protoporphyrin (ZnPP) enhanced the therapeutic efficacy of anti-PD-1 antibodies in a hepatocellular carcinoma mouse model (Du et al. 2025). It is worth noting that in ovarian cancer, the immunomodulatory effects mediated by HMOX1 exhibit significant context-dependency: HMOX1 expression is decreased in ovarian cancer epithelial cells but upregulated in macrophages. Both pathways ultimately inhibit CD8+ T cell activation. Specifically, the inhibition of HMOX1 in ovarian cancer epithelial cells promotes M2 macrophage polarization through increased secretion of TGF-β1. Therefore, despite the opposing expression patterns of HMOX1 in ovarian cancer epithelial cells versus macrophages, its function in promoting an immunosuppressive microenvironment remains consistent (Liu et al. 2025).
In addition to immune cells, HMOX1 may also influence non-immune components of the tumor microenvironment, such as CAFs. Upregulated HMOX1 leads to iron accumulation; iron-loaded cancer-associated fibroblasts (FerroCAFs) secrete myeloid cell-associated proteins (MASP), which inhibit T cell function and contribute to an immunosuppressive environment (Zhang et al. 2024) (Fig. 1).
Through mechanisms such as regulating macrophage polarization and immunosuppression, HMOX1 systemically reshapes the tumor microenvironment, ultimately promoting tumor resistance to immunotherapy. The combination of HMOX1 targeting with ICIs represents a potential strategy to reverse the immunosuppressive tumor microenvironment and overcome therapeutic resistance.

This schematic illustrates the multifaceted mechanisms of HMOX1 in drug resistance. The expression of HMOX1 is regulated by upstream transcription factors such as Nrf2, HIF-1α, and Bach1. HMOX1 catalyzes the degradation of heme (LH) into biliverdin, CO, and Fe²+. The downstream effects include: (1) Antioxidant Stress Response: Biliverdin is converted to bilirubin by biliverdin reductase A, which scavenges ROS to exert an antioxidant effect. (2) Induction of Ferroptosis: Excessive accumulation of free iron leads to the buildup of lipid peroxides, triggering ferroptosis. (3) Modulation of Apoptosis: The dual role of CO in both inhibiting and promoting apoptosis. (4) Modulation of Angiogenesis: The dual role of CO in both promoting and inhibiting angiogenesis. (5) Remodeling of the Immune Microenvironment: Expression of HMOX1 in immune cells, such as macrophages, contributes to the formation of an immunosuppressive tumor microenvironment.

Interventional strategies and drug development targeting HMOX1
Given the role of HMOX1 in drug resistance, interventional strategies against it are primarily divided into two categories: one is to inhibit its protective functions to weaken the defensive capabilities of tumor cells, and the other is to exploit its cytotoxic potential to kill tumor cells under specific conditions. Furthermore, indirect regulatory strategies targeting its upstream and downstream networks also show broad prospects.

HMOX1 inhibitors

Metalloporphyrin inhibitors
Metalloporphyrin compounds, such as ZnPP and tin mesoporphyrin (SnMP), are among the earliest and most widely studied competitive inhibitors of HMOX1, capable of competitively inhibiting its enzymatic activity (Wong et al. 2011). Studies have shown that SnMP inhibits chemotherapy-induced immunosuppression of CD8+ T cells by suppressing HMOX1 activity in the tumor myeloid compartment (Muliaditan et al. 2018). ZnPP has demonstrated synergistic effects with chemotherapeutic agents in various tumor models, enhancing anti-tumor efficacy (Kongpetch et al. 2016; Miyake et al. 2010).
Despite their promising therapeutic effects, these compounds generate singlet oxygen upon light exposure, causing cutaneous photosensitivity, which limits their long-term clinical application. Furthermore, issues such as poor water solubility and safety concerns persist. Additionally, metalloporphyrin compounds also inhibit the HMOX1 isozyme, HMOX2, resulting in poor selectivity (Poudel and Adhikari 2022).

Advances in the research of non-porphyrin small-molecule inhibitors
To overcome the drawbacks of metalloporphyrins, non-porphyrin small-molecule inhibitors have begun to be utilized in research. These inhibitors, which feature a non-competitive binding mode (e.g., VP13/47), exhibit significant inhibitory activity against HMOX1 and possess favorable pharmacokinetic profiles. They can reduce the viability of lung cancer cells and induce apoptosis mediated by glutathione (GSH) depletion and increased oxidative stress (Spampinato et al. 2020), However, such small-molecule inhibitors are rarely reported, and their efficacy, specificity, and safety require further investigation.

Application strategies for inhibitors
In tumor models where HMOX1 is aberrantly overexpressed and represents a critical dependency for survival, HMOX1 inhibitors alone have demonstrated certain anti-tumor effects (Cheng et al. 2025). However, a more common application is the combination of HMOX1 inhibitors with conventional chemotherapy or targeted therapy to achieve a synergistic killing of tumor cells. In hepatocellular carcinoma, ZnPP reverses the polarization of TAMs to the M2 phenotype and reduces the recruitment of Tregs, thereby showing the potential to enhance the efficacy of anti-PD-1 therapy for hepatocellular carcinoma (Du et al. 2025). In pancreatic ductal adenocarcinoma (PDAC), HMOX1 inhibition sensitizes gemcitabine-resistant PDAC cells to nab-paclitaxel-gemcitabine (NPG) (Ahmad et al. 2021).

HMOX1 inducers and agonists

Heme analogs
Studies have reported that two-dimensional nanosheets, modified for effective targeting of liver cancer cells, can be utilized. Upon cellular uptake of Cu-Hemin-PEG-LA, the nanosheets degrade into heme and copper ions within the weakly acidic environment of the lysosome. The released heme upregulates HMOX1 protein expression, increases intracellular Fe²+ levels, and depletes the antioxidant GSH. This, in turn, triggers an increase in lipid ROS and induces ferroptosis, ultimately demonstrating significant anti-tumor effects both in vitro and in vivo (Li et al. 2021a, b). Heme analogs, such as heme arginate, can upregulate HMOX1 mRNA and protein levels, and their safety has been confirmed in randomized controlled clinical trials (Andreas et al. 2018; Thomas et al. 2016). However, their application in oncology has not yet been reported.

Natural products
Many natural products, such as the extract of Artesunate (Liu et al. 2024a, b, c, d), curcumin (Wu et al. 2025), and shikonin (Lu et al. 2024), have been shown to induce HMOX1 expression by activating pathways like Nrf2 and HIF-1α. In vitro studies have demonstrated that shikonin and cisplatin act synergistically to reduce the viability of cisplatin-resistant cells, with the mechanism involving the induction of ferroptosis through HMOX1-mediated upregulation of Fe²+ (Ni et al. 2023). In cisplatin-resistant NSCLC, wogonin participates in ferritinophagy and macrophage immunity via the Keap1-Nrf2/HMOX1 axis, thereby increasing the sensitivity of NSCLC to cisplatin (Chen et al. 2024). However, natural products typically possess multi-target properties and complex mechanisms; their synergistic effects in drug resistance are partially attributed to the regulation of HMOX1.

Others
GSK-J4, a small molecule identified through the integrated screening of a small-molecule inhibitor library and a drug CRISPR library, synergistically promotes HMOX1 expression and increases intracellular Fe²+ levels with donafenib in hepatocellular carcinoma, ultimately leading to ferroptosis (Zheng et al. 2023).

Application strategies for inducers
The simple induction of HMOX1 during the initial stages of tumor therapy may enhance the protective capacity of tumor cells, which is closely linked to the antioxidant, anti-apoptotic, and cytoprotective effects mediated by HMOX1. Metabolites such as CO, produced by HMOX1-catalyzed heme degradation, can scavenge ROS and inhibit apoptosis, thereby promoting tumor cell survival to a certain extent and potentially contributing to the development of tolerance to chemotherapy and radiotherapy. Consequently, HMOX1 inducers may exhibit a “double-edged sword” effect at different stages: they can induce anti-tumor effects such as ferroptosis, but they may also exert pro-survival and tumor-protective effects in the early phases.
Against this backdrop, combination therapy is considered a more rational application strategy. The use of HMOX1 inducers prompts tumor cells to overexpress HMOX1, leading to the sustained release of free iron, which promotes lipid peroxidation and induces ferroptosis (Wei et al. 2021). By employing these inducers in conjunction with other cancer treatment modalities, synergistic therapeutic effects can be achieved (Zhou et al. 2024). Therefore, during the use of inducers, factors such as dosage, timing of administration, and tumor type should be carefully considered to balance potential risks with clinical benefits.

Indirect targeting strategies based on the HMOX1 regulatory network
Given that Nrf2 is the primary transcriptional activator of HMOX1, Nrf2 inhibitors can suppress HMOX1 expression at its source. The small-molecule compound ML385 can inhibit Nrf2 and restore the sensitivity of resistant lung cancer cell lines to cisplatin (Zuo et al. 2025). It has a similar effect in tamoxifen-resistant breast cancer, enhancing the sensitivity of MCF-7 tamoxifen-resistant cells to tamoxifen by inhibiting the Nrf2/HMOX1 pathway (Yuan et al. 2025).
TBE56 is a potent compound that targets Bach1, inducing its degradation in various cancer cells and thereby upregulating HMOX1 expression. Concurrently, TBE56 inhibits cancer cell migration and invasion in a Bach1-dependent manner (Moreno et al. 2022).

Nanotechnology and targeted delivery systems
Although strategies targeting HMOX1 hold great promise, their clinical translation faces significant challenges: small-molecule regulators (especially metalloporphyrins) suffer from poor water solubility, high systemic toxicity, low accumulation in tumor tissues, and a lack of specificity (Poudel and Adhikari 2022). Nanotechnology and targeted delivery systems offer solutions to overcome these obstacles. Research indicates that nanoparticles of approximately 100 nanometers in size have an ideal circulation time and accumulate at tumor sites via the enhanced permeability and retention (EPR) effect (Fan et al. 2025).
Water-soluble ZnPP derivatives, PEG-ZnPP and SMA-ZnPP, can preferentially accumulate at tumor sites through the EPR effect. Both SMA-ZnPP and PEG-ZnPP micelles localize to the endoplasmic reticulum and inhibit HMOX1 in a similar manner, exhibiting potent anti-tumor activity upon intravenous administration (Nakamura et al. 2011).
AbDA-Lim, a bio-nano-composite composed of albumin, polydopamine, and limonene, enters cancer cells facilitated by the affinity of albumin. Subsequently, the released polydopamine enhances HMOX1 expression to degrade heme and promotes the conversion of Fe³+ to Fe²+. Concurrently, limonene reduces GSH levels by inhibiting cystathionine-beta-synthase (CBS), thereby triggering the release of Fe²+ from its GSH-bound storage state into the labile iron pool (LIP). The augmentation of the LIP ultimately induces atypical ferroptosis in cancer cells (Wang et al. 2025).
iCoDMSN is created by preparing cobalt oxide nanodots from bovine serum albumin and cobalt chloride, which are then coupled with an iRGD peptide and loaded into dendritic mesoporous silica nanoparticles. This system upregulates HMOX1, leading to Fe²+ accumulation and the initiation of ferroptosis, and holds promise for achieving synergistic sensitization effects with radiotherapy (Zhao et al. 2023).

Clinical translation and perspectives

Current status and challenges in clinical research

Review and analysis of relevant clinical trials
To date, clinical trials directly targeting HMOX1 as a clear objective remain scarce. Most related studies have focused on heme arginate, an inducer of HMOX1, but its indications are not for cancer (Andreas et al. 2018). A few clinical observations have found that in certain tumor tissues (such as colorectal, lung, and pancreatic cancer), high HMOX1 expression is associated with poor prognosis and therapeutic resistance (Berberat et al. 2005; Degese et al. 2012; Tsai et al. 2012; Yin et al. 2014). It is worth noting that in kidney renal clear cell carcinoma (KIRC), high HMOX1 expression is conversely associated with a favorable prognosis (Men et al. 2025). This reveals the functional heterogeneity of HMOX1 across different cancer types and stages, and also provides indirect clinical evidence for its role as a prognostic biomarker and therapeutic target. However, clinical trials that use HMOX1 modulators to overcome tumor resistance have not yet been reported in the literature.

Challenges ahead
The translation of this field to the clinic faces several core challenges. (1) Drug Selectivity: Metalloporphyrin inhibitors exhibit poor selectivity for HMOX1 and have associated phototoxicity issues, making them unsuitable for long-term clinical use (Poudel and Adhikari 2022). The development of novel, highly selective, and low-toxicity small-molecule inhibitors is an urgent priority. (2) Systemic Toxicity: HMOX1 plays crucial physiological roles in multiple tissues and organs throughout the body (Ryter 2022). Systemic inhibition of HMOX1 may interfere with normal heme metabolism and iron cycling, leading to potential toxicity. Conversely, systemic over-induction of HMOX1 carries the risk of causing systemic oxidative damage. (3) Lack of Biomarkers: There is a lack of biomarkers capable of accurately predicting the efficacy of HMOX1-targeted therapy. Not all tumors with high HMOX1 expression are dependent on this pathway for survival, nor is the ferroptosis-inducing strategy suitable for all patients. Identifying the patient populations most likely to benefit is the key bottleneck to achieving precision therapy.

Future directions and outlook

Development of biomarkers
Future research must focus on developing a multidimensional biomarker system. This includes: (1) Baseline Expression Levels: Assessing the baseline expression of HMOX1 in tumor tissue through immunohistochemistry (IHC) or RNA sequencing. (2) Pathway Activity Status: Evaluating the overall activity of the pathway by detecting the nuclear translocation of Nrf2, the reporter gene activity of ARE elements, or the levels of downstream products (such as bilirubin). (3) Iron Metabolism Status: The analysis of ferritin levels, free iron levels, and the expression profiles of key ferroptosis genes in tumor tissues aims to provide a reference basis for the application of ferroptosis-inducing strategies.
Based on the detection results of the aforementioned biomarkers, attempts will be made to stratify the patient population, such as into an HMOX1 high-expression group and a ferroptosis-sensitive group. Integrating the detection results from the aforementioned three dimensions, patients can be further subdivided into high-sensitivity, intermediate-sensitivity, and low-sensitivity groups. Through this stratification method, future clinical trials may be able to more precisely identify subgroups most likely to benefit from HMOX1-targeted therapy, thereby increasing the success rate of clinical trials and achieving individualized treatment. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) can be adopted as primary outcome measures to comprehensively evaluate therapeutic effects.

Combination therapeutic strategies
Given the potential therapeutic limitations of targeting HMOX1 alone, its clinical application prospects may lie more in combined treatment strategies. (1) Combination with Conventional Therapies: Co-administering HMOX1 inducers or inhibitors with first-line chemotherapeutic or targeted agents can restore tumor sensitivity to standard treatments. (2) Combination with ICIs: In light of the reshaping effect of HMOX1 on the tumor immune microenvironment (Liu et al. 2025), the combined use of HMOX1 inhibitors and PD-1/PD-L1 antibodies is expected to alleviate immunosuppression, improve the tumor microenvironment, and thereby enhance the efficacy of immunotherapy (Fig. 2). However, the efficacy and safety of these combination strategies still require validation through rigorous clinical trials.

This flowchart illustrates a process where patients are stratified based on integrated analysis of HMOX1 expression, pathway activity, and iron metabolism status. This stratification guides the selection of combination therapies—either HMOX1 inhibition or induction. The treatment is delivered via nanocarriers and dynamically monitored to achieve the ultimate goal of improved prognosis.

Conclusion
This review systematically summarizes the complex role of HMOX1 in tumor drug resistance. Current evidence indicates that HMOX1, through its metabolite network, mediates multiple pro-survival mechanisms, including enhanced antioxidant stress (Mancuso 2025), inhibition of apoptosis (Jain et al. 2025), promotion of angiogenesis (Dulak et al. 2008), and remodeling of the immunosuppressive microenvironment (Liu et al. 2025). Its abnormally high expression, observed in various cancer types and treatment contexts, shows a certain correlation with clinical drug resistance and poor prognosis (Mei et al. 2025). Therefore, targeting the HMOX1 pathway provides a theoretical basis worth further exploration and a potential intervention direction for reversing tumor drug resistance.
HMOX1 exhibits significant functional complexity in tumor biology, and whether it exerts a cytoprotective or cytotoxic effect appears to be strictly dependent on the cellular stress intensity, metabolic state, and iron homeostasis (Luu Hoang et al. 2021). This inherent uncertainty means that strategies to reverse drug resistance should not be a simple “one-size-fits-all” approach of inhibition or activation. On one hand, inhibiting its activity may weaken the tumor’s defensive barrier, thereby sensitizing it to conventional therapies; on the other hand, strategically inducing its overexpression under specific conditions could theoretically utilize the released free iron to trigger ferroptosis, thus reversing resistance. However, the specific intervention effects are highly dependent on the precise assessment of the tumor’s specific context. Table 1 summarizes therapeutic strategies tailored to specific cancer types and molecular profiles, serving as a reference for the design of future combination therapies.

It is worth noting that current research still has certain limitations. First, the specific regulatory mechanisms of HMOX1 in different tumor microenvironments and the critical points of its functional switch are not yet fully understood, which may limit the universality of intervention strategies. Second, the selectivity, pharmacokinetic properties, and potential off-target effects of existing HMOX1 modulators (such as ZnPP) still need to be optimized, which may limit their clinical translation. In addition, most current evidence still comes from preclinical studies, lacking support from large-scale clinical trial data, and the physiological protective function of HMOX1 in normal tissues makes systemic targeted therapy potentially face safety challenges.
To translate HMOX1’s targeting potential into clinical benefits, future research needs to focus on the following three levels. (1) Deepening Mechanistic Understanding: Further elucidate the precise regulatory networks of HMOX1 in different tumor subtypes and microenvironments, and clarify the decisive factors that determine its protective or cytotoxic functions. (2) Advancing drug development: Develop novel small-molecule modulators with high selectivity and low toxicity, and utilize nanodelivery systems to enhance drug accumulation in tumor sites, thereby reducing side effects on normal tissues. (3) Optimizing Clinical strategies: The core lies in exploring reliable biomarkers to guide patient stratification and designing rational combination therapies. The combination with chemotherapy, targeted therapy, and ICIs must be based on precise timing and indication selection to balance efficacy and safety.
In summary, targeting HMOX1 is a promising emerging direction in the field of tumor drug resistance treatment. Although it currently faces challenges such as mechanistic complexity and drug development, through interdisciplinary collaboration and in-depth clinical translational research, intervening in the HMOX1 pathway is expected to provide new ideas and strategies for overcoming tumor drug resistance.