Aug 2026· The FEBS Journal· 0 citations· 29 references
Medicine
TL;DR
This work provides a powerful visualizable platform to dynamically study the crosstalk between HIF-1α and ferroptosis in liver cancer, facilitating the exploration of hypoxia-ferroptosis interplay in hepatocarcinogenesis and therapeutic response.
Abstract
Hypoxia, a hallmark of the solid tumor microenvironment (TME), drives malignant progression and confers therapy resistance. In liver cancer, the hypoxia-inducible factor-1α (HIF-1α) has been implicated in suppressing ferroptosis, a key mechanism of therapy resistance; however, its precise regulatory network remains elusive. To systematically identify novel mediators within the HIF-1α-ferroptosis axis, we integrated bioinformatic analyses of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets with experimental validation in hypoxic cells. This strategy identified ATG7 and KDM5C as core hypoxia-responsive genes. ATG7, a key autophagy regulator, also maintains iron homeostasis and modulates oxidative stress, while the histone demethylase KDM5C regulates metabolic and antioxidant gene expression. To functionally dissect their roles, we engineered a novel dual-fluorescence reporter system in HepG2 cells. This system utilizes a synthetic HIF-1α responsive promoter, comprising five tandem repeats of the hypoxia response element (HRE), to drive EGFP expression, thereby reporting hypoxic signaling. Concurrently, the activity of the ATG7 or KDM5C promoter is reported by miRFP670. The resulting cell lines (HepG2-ATG7p-miRFP670-5HRE-EGFP and HepG2-KDM5Cp-miRFP670-5HRE-EGFP) thus visually couple promoter activity with the HIF-1α-mediated hypoxic response. Our work provides a powerful visualizable platform to dynamically study the crosstalk between HIF-1α and ferroptosis in liver cancer, facilitating the exploration of hypoxia-ferroptosis interplay in hepatocarcinogenesis and therapeutic response.
NRF2 is a master regulator of redox and metabolic homeostasis that protects normal tissues from stress but is frequently hijacked by cancers to sustain survival and therapy resistance. Although NRF2 is dispensable for normal tissue function, its role in maintaining cancer cells within the native tumor microenvironment has remained undefined. Here, we uncover an essential and previously unrecognized tumor-specific dependency on NRF2. Using an inducible KrasFSF.G12D/+;Nrf2Fl/Fl;Rosa26CreERT2/CreERT2 (KNR) mouse lung cancer model, we demonstrate that NRF2 deletion alone, without pharmacologic intervention, eradicates cancer cells, reduces tumor burden, and prolongs survival. Single-cell RNA sequencing coupled with artificial intelligence–based genotype classification revealed that NRF2-deleted cancer cells are selectively eliminated, whereas non-cancerous cells tolerate NRF2 loss. Mechanistically, NRF2 deletion induces ferroptosis, a regulated iron-dependent cell death pathway, evidenced by induction of canonical ferroptotic genes (Ptgs2, Acsl4, Tfrc) and protein markers (SO2/3-PRDX3, COX2, TfR1). Importantly, these data support that NRF2 loss induces ferroptotic cell death in vivo within established tumors, in the absence of exogenous ferroptosis inducers or external stress. These findings establish that cancer cells depend on NRF2 to suppress intrinsic ferroptotic stress for survival, a dependency not shared by normal tissues. This discovery fundamentally redefines the pathological role of NRF2 and positions NRF2 inhibition as a standalone, tumor-selective therapeutic strategy to eliminate Kras-driven malignancies by unleashing ferroptosis.
Dichun Huang, Mae Zhang, Ben N Stansfield et al.· Redox Biology· 0 citations
Ferroptosis, an iron-dependent form of regulated cell death driven by excessive lipid peroxidation, has emerged as a critical determinant of cancer drug resistance. While significant progress has been made in understanding the core biochemical pathways of ferroptosis, the transcriptional and epigenetic mechanisms governing ferroptosis sensitivity in drug-resistant cancer cells remain incompletely understood. This review provides a comprehensive analysis of the transcriptional regulatory networks (Nrf2, YY1, p53, HIF-1α) and epigenetic modifications (DNA methylation, histone modifications, non-coding RNAs, chromatin remodeling) that orchestrate ferroptosis programs in drug resistance. Critically, we propose that transcriptional-epigenetic crosstalk represents the core driver of ferroptosis plasticity, enabling cancer cells to dynamically adapt to therapeutic stress. We integrate our team's original findings on YY1/YY2 homeostatic regulation of ferroptosis in colorectal cancer drug resistance and discuss the dual role of ferroptosis-both lethal and sublethal-in shaping tumor evolution and therapeutic outcomes. Furthermore, we systematically analyze preclinical and clinical progress in targeting transcriptional and epigenetic regulators to sensitize drug-resistant cancers to ferroptosis, highlighting rational combination strategies and major clinical translation bottlenecks. Finally, we propose five concrete future research directions that will advance the development of ferroptosis-based precision cancer therapy. This review bridges mechanistic epigenetic biology with translational pharmacology, providing a valuable reference for overcoming cancer drug resistance.
Ze-Nan Xu, Man-Xuan Zhang, Muhammad Faseeh et al.· Biochemical Pharmacology· 0 citations
Glioma represents one of the most aggressive tumors in the central nervous system, with clinical management facing significant challenges including high recurrence rates and therapeutic resistance. Ferroptosis, an iron-dependent form of cell death, holds potential for glioma treatment, yet tumor cells frequently develop evasion mechanisms. This study elucidates the molecular mechanisms by which hypoxic microenvironment confers ferroptosis resistance in glioma cells, focusing on the pivotal role of the HIF-1α/SREBP1 signaling axis and its downstream effectors FASN and SCD1. Our experimental results demonstrate that hypoxic conditions significantly upregulate HIF-1α expression and confer resistance to RSL3-induced ferroptosis. Mechanistic studies reveal that HIF-1α promotes SREBP1 activation, which subsequently upregulates FASN and SCD1 expression to suppress lipid peroxidation.Furthermore, the HIF-1α-specific inhibitor PX-478 effectively reverses hypoxia-induced ferroptosis resistance and significantly enhances tumor cell sensitivity to ferroptosis inducers. In vivo experiments confirm the potent antitumor effects of PX-478 combined with RSL3. This study systematically elucidates the role of the HIF-1α-SREBP1-FASN/SCD1 signaling axis in ferroptosis regulation in glioma, providing important theoretical foundations and experimental support for developing HIF-1α-targeted ferroptosis therapies.
Zhong-Jun Shen, Yao Zhao, Mingbo Jia et al.· Journal of Lipid Research· 0 citations
Ferroptosis, a form of oxidative cell death, represents a therapeutic vulnerability for treating apoptosis-resistant cancers. Here, we identify leucine zipper transcription factor-like 1 (LZTFL1) as a key regulator of ferroptosis that rewires glutathione (GSH) metabolism. Mechanistically, LZTFL1 promotes oxidation of glucose-6-phosphate dehydrogenase (G6PD), thereby limiting NADPH production and impairing GSH regeneration. GSH depletion in turn enhances LZTFL1 translation via an AKT-mammalian target of rapamycin (mTOR)-eukaryotic initiation factor 4E (eIF4E) pathway, establishing a feedforward loop that amplifies ferroptosis. In vivo, the LZTFL1-formin homology 2 domain-containing 1 (FHOD1)-G6PD axis sensitizes multiple tumor models, including patient-derived xenografts, to ferroptosis, leading to enhanced lipid peroxidation, reduced GSH levels, suppressed tumor growth, and prolonged survival. LZTFL1 expression restores cisplatin sensitivity in resistant lung and ovarian cancer cells and predicts improved survival outcomes in patients with lung adenocarcinoma. Moreover, FDA-approved agents upregulate LZTFL1 and re-sensitize resistant tumors to cisplatin. These findings highlight LZTFL1 as a potential biomarker and a therapeutic target for enhancing ferroptosis-based cancer therapy.
Xiangfei Xue, Xiao Zhang, Qianjun Zhou et al.· Molecules and Cells· 0 citations
The activation of ferroptosis, a cell death mechanism driven by excessive ferrous ions (Fe2+) and lipid peroxides, has emerged as a promising target for cancer treatment. However, in the case of quantitative regulation of target genes, it remains uncertain whether ferroptosis can be induced in bladder cancer (BCa) cells without affecting normal ones. We investigated this using an innovative CRISPR‐dCas9 system to upregulate and downregulate the ferroptosis‐related gene BECN1 and OTUB1, respectively. We identified two genes that can affect and promote ferroptosis‐related pathways, analysing their expression in bladder tissue through The Cancer Genome Atlas. Our unique CRISPR‐dCas9 technology, under the control of an hTERT promoter, selectively adjusted BECN1 and OTUB1 expression exclusively in cancer cells. RT‐qPCR and western blotting demonstrated significant alterations in the expression of GPX4 and SLC7A11, proteins strongly associated with ferroptosis, in BCa cells, while normal bladder cells remained unaffected. We developed a quantitative model based on synthetic biology principles to describe the regulatory relationships between the ferroptosis‐related genes BECN1 and OTUB1 and their downstream targets GPX4 and SLC7A11 in bladder cancer cells. The model establishes a direct proportional relationship between BECN1 upregulation and decreased GPX4 expression, and between OTUB1 downregulation and decreased SLC7A11 expression. In vitro experiments revealed reduced viability, proliferation, migration, and invasion in UMUC‐3 and T24 BCa cells. Importantly, Fer‐1 and DFO rescued the viability loss, and C11‐BODIPY staining confirmed increased lipid ROS accumulation, supporting ferroptosis‐associated cell death following BECN1/OTUB1 regulation. In vivo xenograft experiments showed that BECN1 upregulation or OTUB1 downregulation suppressed tumour growth. Tumour‐tissue immunofluorescence further showed reduced GPX4 expression in BECN1‐upregulated tumours and reduced SLC7A11 expression in OTUB1‐downregulated tumours, supporting suppression of the GPX4/SLC7A11 ferroptosis‐protective axis in vivo. The quantitative equation derived from our data suggests that the induction of ferroptosis in bladder cancer cells can be effectively modulated by these two genes, and the experimental results also indicate our system can modulate these two genes to affect the function of BCa cells without affecting the normal cells, offering a promising new direction for the development of targeted therapy for bladder cancer.
Ying Dong, Chao Xu, Bing Yan et al.· Journal of Cellular and Mole...· 0 citations
Ferroptosis, an iron-dependent form of regulated cell death, is increasingly recognized as a context-dependent therapeutic vulnerability in cancer, particularly as malignant cells adapt to oxidative, metabolic, and therapy-induced stresses. As a prevalent and reversible epitranscriptomic modification, RNA N6-methyladenosine (m6A) modification orchestrates RNA stability, translation, splicing and decay; consequently, its dysregulation contributes to cancer progression and therapeutic resistance. The intersection of m6A regulation and ferroptosis is therefore biologically important because many ferroptosis threshold genes are short-lived, stress-responsive transcripts controlled by writers, erasers, readers and RNA-binding proteins. This review synthesizes empirical evidence elucidating how m6A regulators remodel cystine import, GPX4-dependent antioxidant defense, FSP1 signaling, lipid metabolism, iron handling, autophagy and tumor-microenvironmental communication. We organize the evidence by regulatory layer rather than cancer type, covering writer-mediated deposition, reader and RNA-binding protein recognition, eraser-dependent demethylation, non-coding RNA and exosomal regulation, and downstream ferroptosis modules. We further discuss how this axis contributes to radiotherapy, chemotherapy, targeted-therapy resistance and ferroptosis-sensitizing combinations. Although m6A-ferroptosis crosstalk offers promising biomarker and therapeutic opportunities, translation requires transcript-level validation, standardized ferroptosis assays, tumor-selective delivery and clinically meaningful patient stratification. A deeper and more precise integration of epitranscriptomics with ferroptosis biology holds the potential to transform stress-adaptive RNA circuits into actionable vulnerabilities for precision cancer therapy.
Qing-Miao Shi, Yang-Ni Li, Chao Guan· Frontiers in Cell and Develo...· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
