2. Academic Validation
  3. Liver cancer chronically exposed to palmitate acquires ferroptosis resistance via the downregulation of glutamine-driven hepcidin expression

Liver cancer chronically exposed to palmitate acquires ferroptosis resistance via the downregulation of glutamine-driven hepcidin expression

  • Metabolism. 2025 Dec 17:176:156469. doi: 10.1016/j.metabol.2025.156469.
Dong-Ho Kim 1,  Mi Kyung Kim 2,  Daehoon Kim 3,  Eun-Jun Kwon 3,  Jieun Shin 1,  Sebin Lee 1,  Bae-Gon Kang 4,  Jae Won Yun 5,  Jaebon Lee 5,  Hye Won Lee 6,  Byoung Kuk Jang 2,  Ghilsuk Yoon 7,  Kwang-Hyeon Liu 8,  Jun-Kyu Byun 9,  Yeon-Kyung Choi 10,  Keun-Gyu Park 11
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, 41566, South Korea.
  • 2 Department of Internal Medicine, Keimyung University School of Medicine, Daegu, 42601, South Korea.
  • 3 Department of Biomedical Science, Kyungpook National University, Daegu, 41566, South Korea.
  • 4 BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit and College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, South Korea.
  • 5 Veterans Health Service Medical Research Institute, Veterans Health Service Medical Center, Seoul, 05368, South Korea.
  • 6 Department of Pathology, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine, Daegu, 42601, South Korea.
  • 7 Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, 41404, South Korea.
  • 8 BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit and College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, South Korea; Mass Spectrometry Based Convergence Research Institute, Kyungpook National University, Daegu, 41566, South Korea.
  • 9 Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, 41566, South Korea; Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, 41566, South Korea. Electronic address: [email protected].
  • 10 Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, 41566, South Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, 41404, South Korea. Electronic address: [email protected].
  • 11 Department of Biomedical Science, Kyungpook National University, Daegu, 41566, South Korea; Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, 41566, South Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, South Korea. Electronic address: [email protected].
PMID: 41418943 DOI: 10.1016/j.metabol.2025.156469
Abstract

Background: Immune checkpoint blockade (ICB) has revolutionized treatment of hepatocellular carcinoma (HCC), but its efficacy remains limited. Recent studies demonstrate that resistance to Ferroptosis is a significant barrier to the success of ICB.

Methods: Ferroptosis was assessed by measuring C11-BODIPY fluorescence and 4-hydroxynonenal (4-HNE) staining. Epigenetic regulation of hepcidin under fatty acid-rich conditions in HCC cells was investigated through chromatin immunoprecipitation and histone methylation analyses. Clinical relevance was evaluated using ICB response datasets and analyses of tumor tissues from HCC patients.

Results: We demonstrate that prolonged exposure to high palmitate concentrations induces Ferroptosis resistance in HCC cells by altering glutamine availability. Mechanistically, chronic exposure to palmitate and high-fat diet-feeding reduced glutamine-derived α-KG concentrations in HCC cells, leading to a H3K27me3-mediated reduction in hepcidin and depletion of the intracellular labile iron pool, thereby promoting resistance to anti-programmed death-ligand 1 (anti-PD-L1)-induced Ferroptosis. This resistance was reversed by the EZH2 Inhibitor tazemetostat, which epigenetically restored hepcidin expression in both in vitro and in vivo models. Notably, tumor tissues from HCC patients exhibited high FFA levels, along with low levels of glutamine, hepcidin, and iron, which correlated with shorter overall survival. H3K27me3-mediated suppression of hepcidin was further confirmed in patient cohorts.

Conclusion: Our study uncovers a previously unrecognized type of palmitate-induced metabolic reprogramming that confers resistance to ICB-induced Ferroptosis on HCC, and propose a therapeutic strategy to overcome Ferroptosis resistance under free fatty acid-rich conditions.

Keywords

Ferroptosis; Glutamine; Hepatocellular carcinoma; Hepcidin; Immune checkpoint blockade; Palmitate.

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