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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年9月30日

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  • Jie Li,
  • Shengwei Mao,
  • Shiguang Yang,
  • Yunwei Lou,
  • Xuhui Zhao,
  • Jiafeng Chen,
  • Yichao Bu,
  • Bei Lv,
  • Qing Shi,
  • Yunjie Zhang,
  • Xingxing Zhang,
  • Zhijie Yu,
  • Yuan Fang,
  • Jinglin Xia

摘要

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.