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Targeting JMJD6/PPARγ/GPX4 axis overcomes ferroptosis resistance and enhances therapeutic efficacy in hepatocellular carcinoma

Oncogene (2025)Cite this article

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Abstract

Despite ferroptosis induction being a promising strategy for hepatocellular carcinoma (HCC), its clinical application is limited by intrinsic resistance mechanisms. Through CRISPR-Cas9 screening of epigenetic regulators, we identified JMJD6 as a critical mediator of ferroptosis resistance in HCC. JMJD6 knockdown or pharmacological inhibition (iJMJD6) enhanced ferroptosis induced by ferroptosis inducers (erastin and RSL3), as indicated by decreased cell viability, reduced intracellular glutathione levels, increased lipid peroxidation, and disrupted mitochondrial cristae morphology, thereby promoting the susceptibility of HCC to ferroptosis. Clinically, JMJD6 was highly expressed in HCC, and its elevated expression was correlated with a poor prognosis in HCC. Mechanistically, JMJD6 interacts with BRD4, forming a transcriptional complex that binds to the PPARγ promoter. Through its demethylase activity, JMJD6 reduces H4R3me2s levels at the promoter, thereby promoting PPARγ transcription, activating the PPARγ-GPX4 axis to enhance lipid peroxidation scavenging and ferroptosis resistance. Given the role of ferroptosis in resistance mechanisms of molecular-targeted therapies, we combined iJMJD6 with sorafenib or lenvatinib, demonstrating enhanced ferroptosis and potent suppression of HCC proliferation in vitro and in vivo. Our findings revealed the JMJD6/PPARγ/GPX4 axis as a key driver of ferroptosis resistance and established JMJD6 targeting as a novel strategy to improve ferroptosis-based HCC therapies.

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Fig. 1: CRISPR-Cas9 screening identifies JMJD6 as an anti-ferroptosis epigenetic regulator in HCC.
Fig. 2: JMJD6 is overexpressed in HCC and correlated with poor prognosis.
Fig. 3: JMJD6-induced ferroptosis resistance is mediated by GPX4.
Fig. 4: JMJD6 regulates GPX4 through PPARγ signaling pathway.
Fig. 5: JMJD6 cooperates with BRD4 to regulate PPARγ transcription in HCC.
Fig. 6: JMJD6 inhibitor potentiates the response of HCC to ferroptosis inducers.
Fig. 7: JMJD6 inhibitor potentiates the response of HCC to molecular-targeted therapies.
Fig. 8: A working model of HCC promotes tumor ferroptosis resistance via activation of the JMJD6-PPAR-GPX4 axis.

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Data will be made available to qualified researchers upon request. Researchers interested in accessing the data should submit a methodologically sound research proposal to the corresponding author.

References

  1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63.

    PubMed  Google Scholar 

  2. Yang C, Zhang H, Zhang L, Zhu AX, Bernards R, Qin W, et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2023;20:203–22.

    Article  PubMed  Google Scholar 

  3. Teufel A, Kudo M, Qian Y, Daza J, Rodriguez I, Reissfelder C, et al. Current trends and advancements in the management of hepatocellular carcinoma. Dig Dis. 2024;42:349–60.

    Article  PubMed  Google Scholar 

  4. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lei G, Zhuang L, Gan B. The roles of ferroptosis in cancer: tumor suppression, tumor microenvironment, and therapeutic interventions. Cancer Cell. 2024;42:513–34.

    Article  CAS  PubMed  Google Scholar 

  6. Ajoolabady A, Tang D, Kroemer G, Ren J. Ferroptosis in hepatocellular carcinoma: mechanisms and targeted therapy. Br J Cancer. 2023;128:190–205.

    Article  PubMed  Google Scholar 

  7. Liao C, He Y, Luo X, Deng G. Ferroptosis: insight into the treatment of hepatocellular carcinoma. Cancer Cell Int. 2024;24:376.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ma S, Xie F, Wen X, Adzavon YM, Zhao R, Zhao J, et al. GSTA1/CTNNB1 axis facilitates sorafenib resistance via suppressing ferroptosis in hepatocellular carcinoma. Pharmacol Res. 2024;210:107490.

    Article  CAS  PubMed  Google Scholar 

  9. Shi CJ, Pang FX, Lei YH, Deng LQ, Pan FZ, Liang ZQ, et al. 5-methylcytosine methylation of MALAT1 promotes resistance to sorafenib in hepatocellular carcinoma through ELAVL1/SLC7A11-mediated ferroptosis. Drug Resist Updat. 2024;78:101181.

    Article  PubMed  Google Scholar 

  10. Dai W, Qiao X, Fang Y, Guo R, Bai P, Liu S, et al. Epigenetics-targeted drugs: current paradigms and future challenges. Signal Transduct Target Ther. 2024;9:332.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Yang J, Xu J, Wang W, Zhang B, Yu X, Shi S. Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther. 2023;8:210.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Zhou S, Liu J, Wan A, Zhang Y, Qi X. Epigenetic regulation of diverse cell death modalities in cancer: a focus on pyroptosis, ferroptosis, cuproptosis, and disulfidptosis. J Hematol Oncol. 2024;17:22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. He R, Liu Y, Fu W, He X, Liu S, Xiao D, et al. Mechanisms and cross-talk of regulated cell death and their epigenetic modifications in tumor progression. Mol Cancer. 2024;23:267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Veglia Tranchese R, Battista S, Cerchia L, Fedele M. Ferroptosis in cancer: epigenetic control and therapeutic opportunities. Biomolecules. 2024;14:1443.

  15. Beacon TH, Delcuve GP, López C, Nardocci G, Kovalchuk I, van Wijnen AJ, et al. The dynamic broad epigenetic (H3K4me3, H3K27ac) domain as a mark of essential genes. Clin Epigenetics. 2021;13:138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Arnold M, Stengel KR. Emerging insights into enhancer biology and function. Transcription. 2023;14:68–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Liu W, Ma Q, Wong K, Li W, Ohgi K, Zhang J, et al. Brd4 and JMJD6-associated anti-pause enhancers in regulation of transcriptional pause release. Cell. 2013;155:1581–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Pei R, Zhao L, Ding Y, Su Z, Li D, Zhu S, et al. JMJD6-BRD4 complex stimulates lncRNA HOTAIR transcription by binding to the promoter region of HOTAIR and induces radioresistance in liver cancer stem cells. J Transl Med. 2023;21:752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Aprelikova O, Chen K, El Touny LH, Brignatz-Guittard C, Han J, Qiu T, et al. The epigenetic modifier JMJD6 is amplified in mammary tumors and cooperates with c-Myc to enhance cellular transformation, tumor progression, and metastasis. Clin Epigenetics. 2016;8:38.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Xu X, Hoang S, Mayo MW, Bekiranov S. Application of machine learning methods to histone methylation ChIP-Seq data reveals H4R3me2 globally represses gene expression. BMC Bioinforma. 2010;11:396.

    Article  Google Scholar 

  21. Xiao RQ, Ran T, Huang QX, Hu GS, Fan DM, Yi J, et al. A specific JMJD6 inhibitor potently suppresses multiple types of cancers both in vitro and in vivo. Proc Natl Acad Sci USA. 2022;119:e2200753119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bo W, Chen Y. Lenvatinib resistance mechanism and potential ways to conquer. Front Pharm. 2023;14:1153991.

    Article  CAS  Google Scholar 

  23. Wang Y, Yu G, Chen X. Mechanism of ferroptosis resistance in cancer cells. Cancer Drug Resist. 2024;7:47.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Manni W, Jianxin X, Weiqi H, Siyuan C, Huashan S. JMJD family proteins in cancer and inflammation. Signal Transduct Target Ther. 2022;7:304.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Yang J, Chen S, Yang Y, Ma X, Shao B, Yang S, et al. Jumonji domain-containing protein 6 protein and its role in cancer. Cell Prolif. 2020;53:e12747.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wang K, Yang C, Li H, Liu X, Zheng M, Xuan Z, et al. Role of the epigenetic modifier JMJD6 in tumor development and regulation of immune response. Front Immunol. 2022;13:859893.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cioni B, Ratti S, Piva A, Tripodi I, Milani M, Menichetti F, et al. JMJD6 shapes a pro-tumor microenvironment via ANXA1-dependent macrophage polarization in breast cancer. Mol Cancer Res. 2023;21:614–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wan J, Liu H, Yang L, Ma L, Liu J, Ming L. JMJD6 promotes hepatocellular carcinoma carcinogenesis by targeting CDK4. Int J Cancer. 2019;144:2489–2500.

    Article  CAS  PubMed  Google Scholar 

  29. Peng J, Fan B, Bao C, Jing C. JMJD3 deficiency alleviates lipopolysaccharide‑induced acute lung injury by inhibiting alveolar epithelial ferroptosis in a Nrf2‑dependent manner. Mol Med Rep. 2021;24:807.

  30. Zhang C, Ding J, Lim KS, Zhou W, Miao W, Wu S, et al. JMJD6 Rewires ATF4-dependent glutathione metabolism to confer ferroptosis resistance in SPOP-mutated prostate cancer. Cancer Res. 2025; 85:1496–1513.

  31. Koppula P, Zhuang L, Gan B. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy. Protein Cell. 2021;12:599–620.

    Article  CAS  PubMed  Google Scholar 

  32. Luo Y, Bai XY, Zhang L, Hu QQ, Zhang N, Cheng JZ, et al. Ferroptosis in cancer therapy: mechanisms, small molecule inducers, and novel approaches. Drug Des Dev Ther. 2024;18:2485–529.

    Article  Google Scholar 

  33. Zheng J, Conrad M. The metabolic underpinnings of ferroptosis. Cell Metab. 2020;32:920–37.

    Article  CAS  PubMed  Google Scholar 

  34. Zhao Y, Tan H, Zhang X, Zhu J. Roles of peroxisome proliferator-activated receptors in hepatocellular carcinoma. J Cell Mol Med. 2023;28:e18042.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Bai X, Zheng E, Tong L, Liu Y, Li X, Yang H, et al. Angong Niuhuang Wan inhibit ferroptosis on ischemic and hemorrhagic stroke by activating PPARγ/AKT/GPX4 pathway. J Ethnopharmacol. 2024;321:117438.

    Article  CAS  PubMed  Google Scholar 

  36. Chen J, Wang Y, Li M, Zhu X, Liu Z, Chen Q, et al. Netrin-1 alleviates early brain injury by regulating ferroptosis via the PPARγ/Nrf2/GPX4 signaling pathway following subarachnoid hemorrhage. Transl Stroke Res. 2024;15:219–37.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81972233; No. 82373086), Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation (No. 2018E10008) and the Major scientific and technological innovation project of Wenzhou Science and Technology Bureau (No. ZY2021009). Some parts of the figures are created with BioRender.com.

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Author notes

  1. These authors contributed equally: Jie Li, Shengwei Mao, Shiguang Yang, Yunwei Lou.

Authors and Affiliations

  1. Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China

    Jie Li & Jinglin Xia

  2. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China

    Shengwei Mao, Jiafeng Chen, Yichao Bu & Yuan Fang

  3. Department of Hepatobiliary and Pancreatic Surgery, Minhang Hospital, Fudan University, Shanghai, China

    Shiguang Yang

  4. Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China

    Yunwei Lou & Zhijie Yu

  5. College of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, China

    Xuhui Zhao

  6. Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China

    Bei Lv

  7. Department of Gastroenterology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China

    Qing Shi

  8. Department of Radiation Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Yunjie Zhang

  9. Department of Gastroenterology, Shanghai Jiaotong University Affiliated Sixth People Hospital South Campus, Shanghai, China

    Xingxing Zhang

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  1. Jie Li
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Contributions

J. Xia designed the study, secured funding, and supervised the project. J. Li, S. Mao, S. Yang, and Y. Lou performed experiments and analyzed data. J. Li, S. Mao, and Y. Lou wrote the manuscript. S. Yang, X. Zhao, and J. Chen conducted statistical analysis. Y. Fang and Z. Yu reviewed and edited the manuscript. B. Lv, Q. Shi, Y. Zhang, and X. Zhang provided technical and administrative support. All authors read and approved the final manuscript.

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Correspondence to Zhijie Yu, Yuan Fang or Jinglin Xia.

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Li, J., Mao, S., Yang, S. et al. Targeting JMJD6/PPARγ/GPX4 axis overcomes ferroptosis resistance and enhances therapeutic efficacy in hepatocellular carcinoma. Oncogene (2025). https://doi.org/10.1038/s41388-025-03581-z

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