NRF2's Dual Role in Ferroptosis: A Context-Dependent Switch for Cancer Therapy
Key Insights
NRF2 (search) plays a dual, context-dependent role in ferroptosis (search), acting as both a suppressor and promoter of this iron-dependent cell death pathway depending on cellular conditions.
NRF2 (search) suppresses ferroptosis (search) primarily through transcriptional control of SLC7A11 (search), GSH biosynthesis enzymes, and FSP1 (search)/CoQ10 antioxidant systems, contributing to therapy resistance in many cancers.
Paradoxically, NRF2 (search) can promote ferroptosis (search) via HMOX1 (search)-mediated iron accumulation and MRP1-mediated GSH efflux, creating therapeutic vulnerabilities in certain tumor contexts.
The transcription factor NRF2 (search) has long been recognized as a master regulator of cellular antioxidant defense, but emerging evidence reveals a far more nuanced picture: NRF2 can both suppress and promote ferroptosis (search) depending on cellular context, tumor genetics, and the specific downstream effectors engaged. This dual functionality positions NRF2 as a dynamic modulator rather than a simple on-off switch, with profound implications for the rational design of ferroptosis-based cancer therapies.
Since the term "ferroptosis (search)" was coined by Stockwell and colleagues in 2012, describing a regulated, iron-dependent form of cell death morphologically and biochemically distinct from apoptosis and necroptosis, the molecular understanding of this pathway has expanded dramatically. Central to ferroptosis regulation are three key features: the loss of lipid peroxide repair capacity, oxidation of polyunsaturated fatty acid (PUFA)-containing phospholipids, and the availability of redox-active iron. NRF2 (search) intersects with each of these regulatory axes.
NRF2 (search) as a ferroptosis (search) suppressor
The most well-characterized function of NRF2 (search) in ferroptosis (search) is its protective role through the transcriptional control of genes involved in glutathione (GSH) biosynthesis and utilization. NRF2 directly regulates SLC7A11 (search)/xCT, the cystine-glutamate antiporter that imports cystine for GSH synthesis, as well as GCLC, GCLM, GSR, and other enzymes critical for maintaining the GSH-dependent antioxidant system. GPX4 (search), the central ferroptosis regulator, detoxifies membrane lipid hydroperoxides using GSH as a cofactor, making NRF2-mediated GSH production rate-limiting for GPX4 activity.
In non-small cell lung cancer, NRF2 (search) activity led to ferroptosis (search) resistance by inducing GCLM, SLC7A11 (search), GSR, SRXN1, GPX2, and NQO1 gene expression. In triple-negative breast cancer, single-cell transcriptomic analysis revealed NRF2 protects from ferroptosis through activation of GSH-dependent peroxidases including MGST3 and PRDX6. Furthermore, ACTL6A was found to cooperate with NRF2 to regulate GCLC expression, facilitating GSH synthesis and inhibiting ferroptosis in gastric cancer cells.
Beyond the canonical GPX4 (search) pathway, NRF2 (search) also regulates GPX4-independent ferroptosis (search) defense mechanisms. Gan and colleagues identified ferroptosis suppressor protein 1 (FSP1 (search)) as a direct NRF2 target, with its upregulation in KEAP1 (search)-mutant cancers promoting ferroptosis resistance and poor survival. FSP1 reduces ubiquinone (CoQ) to ubiquinol (CoQH2) on the plasma membrane, where CoQH2 serves as a radical-trapping antioxidant that neutralizes lipid peroxyl radicals. In pancreatic ductal adenocarcinoma, high NRF2 expression correlated with elevated FSP1 levels, and NRF2 downregulation combined with FSP1 inhibitors significantly increased ferroptosis sensitivity.
NRF2 (search) also orchestrates iron homeostasis through transcriptional control of FTL, FTH1, SLC40A1, and HMOX1 (search). In KEAP1 (search)-mutant cells resistant to ferroptosis (search), NRF2 activation markedly elevates ferritin heavy and light chain levels. A recent study demonstrated that NRF2 directly drives HERC2 transcription, which binds NCOA4 and inhibits ferritin degradation, thereby limiting the labile iron pool available for Fenton reaction-driven lipid peroxidation.
The pro-ferroptotic face of NRF2 (search)
Paradoxically, NRF2 (search) can promote ferroptosis (search) under certain conditions, with this effect largely mediated through the transcriptional induction of HMOX1 (search). Despite its antioxidant properties, excessive HMOX1 activity can drive Fe²⁺ accumulation, impairing iron homeostasis and triggering ferroptosis. This has been demonstrated across multiple cancer types: withaferin-A promotes ferroptosis in high-risk neuroblastoma via KEAP1 (search) inhibition and HMOX1 upregulation; zoledronic acid triggers ferroptosis in osteosarcoma cells by upregulating HMOX1 and reducing CoQ10; and in hepatocellular carcinoma, GSK-J4 combined with donafenib causes ferroptotic cell death associated with increased NRF2 and HMOX1.
The outcome appears to follow a hormetic response pattern, where moderate HMOX1 (search) induction confers protection, whereas excessive activation becomes detrimental by increasing free iron beyond ferritin's buffering capacity. However, the precise mechanisms by which HMOX1 upregulation, alongside other cytoprotective NRF2 (search) targets, triggers ferroptosis (search) remain unclear.
Another NRF2 (search)-regulated factor with pro-ferroptotic potential is ABCC1 (search), encoding multidrug resistance protein 1 (MRP1). While MRP1 promotes efflux of GSH-drug conjugates contributing to drug resistance, it can also export GSH itself, leading to intracellular GSH depletion. Dixon and colleagues reported that high MRP1 levels confer resistance to pro-apoptotic chemotherapeutics while simultaneously sensitizing cells to ferroptotic inducers such as erastin2, RSL3, ML162, and BSO. Similarly, glioblastoma cells with elevated NRF2 evade temozolomide-induced cell death by increasing GSH-conjugate efflux via MRP1, yet this same mechanism renders them more susceptible to ferroptosis (search) through GSH depletion.
Clinical translation challenges
Despite the therapeutic promise of ferroptosis (search) induction, no ferroptosis inducers have reached clinical application, largely due to challenges in drug bioavailability and tumor-specific targeting. Erastin is unsuitable for in vivo use due to low solubility and metabolic instability, though derivatives such as imidazole ketone erastin with improved pharmacokinetic properties have shown efficacy in fibrosarcoma and lymphoma xenograft models. RSL3 has many off-target effects on other selenoproteins, while FIN56 displays metabolic instability and off-target effects on squalene synthesis.
Direct NRF2 (search) modulation faces similar hurdles. Brusatol, a natural product identified as an NRF2 inhibitor, lacks target specificity. VVD-065, a first-in-class NRF2 inhibitor that covalently targets KEAP1 (search) Cys151, is currently in a Phase I clinical trial (NCT05954312). Conversely, NRF2 activation has shown clinical progress in non-neoplastic diseases, with omaveloxolone becoming the first drug approved for Friedreich's ataxia through NRF2 activation, an effect that may be partly attributable to NRF2-mediated inhibition of ferroptosis (search).
Targeting specific NRF2 (search) downstream effectors offers a more precise approach. Inhibitors of anti-ferroptotic NRF2 targets include EN25, which selectively targets an allosteric cysteine on GCLM; viFSP1, a species-independent FSP1 (search) inhibitor; and salinomycin, which promotes lysosomal iron sequestration in breast cancer stem cells. On the pro-ferroptotic side, hemin—FDA-approved since 1983 for porphyria—promotes HMOX1 (search) upregulation and is being explored for repurposing.
To enhance in vivo efficacy, researchers are exploring nanomedicine delivery strategies. Ultrasmall PEG-coated silica nanoparticles were the first to induce ferroptosis (search) and reduce tumor growth by delivering iron directly into cells, with early clinical trials suggesting safety for human use. Other platforms, including FePt-NP2 and injectable hydrogels such as RTFG@SA, allow targeted delivery of ferroptosis inducers.
The dual role of NRF2 (search) in ferroptosis (search) underscores the importance of tumor context in therapeutic decision-making. Developing gene signatures that predict tumor response to ferroptosis inducers based on NRF2 status and target expression may ultimately guide personalized treatment strategies, optimizing therapeutic windows while minimizing toxicity.