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  3. Deciphering the rules of disulfidptosis: a genome-wide signature for identifying disulfidptosis-related genes and analyzing hepatocellular carcinoma chemotherapy sensitivities

Deciphering the rules of disulfidptosis: a genome-wide signature for identifying disulfidptosis-related genes and analyzing hepatocellular carcinoma chemotherapy sensitivities

  • Free Radic Biol Med. 2025 Oct 23:241:914-932. doi: 10.1016/j.freeradbiomed.2025.10.278.
Yi Zhang 1,  Ying Guo 2,  Wenxi He 3,  Yaping Zhao 4,  Zhaode Feng 3,  Mengjiao Shi 4,  Xinyan Li 4,  Liangwen Yan 4,  Jiayi Xu 4,  Kailing Hu 4,  Rongrong Liu 4,  Yinggang Zhang 4,  Gang Wang 5,  Hao Li 6,  Pengfei Liu 7
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Center for Mitochondrial Biology & Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.
  • 2 Department of Critical Care Medicine, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 3 Center for Mitochondrial Biology & Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China.
  • 4 International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 5 Department of Critical Care Medicine, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Surgical Critical Care and Life Support, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China.
  • 6 Center for Mitochondrial Biology & Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, China. Electronic address: lihao@xjtu.edu.cn.
  • 7 International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education of China, Xi'an, China. Electronic address: liupengfei@xjtu.edu.cn.
PMID: 41138962 DOI: 10.1016/j.freeradbiomed.2025.10.278
Abstract

Disulfidptosis, a novel form of regulated cell death (RCD), represents a promising strategy for Cancer therapy. However, identifying its regulators remains a key challenge. In this study, we constructed a genome-wide Disulfidptosis signature (DS) model using known regulators and large-scale human gene expression data comprising 1454 studies and 272,445 samples. This model predicted Disulfidptosis propensity across 33 Cancer types and highlighted DS differences across tissues and organs. Functional analysis focused on the top 1 % of high-DS and low-DS genes, revealing their sensitivity to perturbations through simulated overexpression and knockout experiments. In hepatocellular carcinoma (HCC), NRF1 and NRF2 were identified as key Disulfidptosis regulators, functioning as a desensitizer and sensitizer, respectively, as validated through gene knockouts, cellular morphology, and functional analyses. Additionally, the ketogenic diet significantly increased cellular sensitivity to Disulfidptosis under glucose starvation by promoting metabolic adaptation. Using network pharmacology, small-molecule compounds influencing Disulfidptosis were identified. Among these, NR-CL was validated as a Disulfidptosis desensitizer, while lomerizine and clioquinol were confirmed as sensitizers through gene expression predictive analyses and cellular functional validation. These findings lay a robust foundation for uncovering novel regulatory mechanisms of Disulfidptosis and provide practical strategies for enhancing Cancer chemotherapy through targeted interventions.

Keywords

Disulfidptosis signature; HCC chemotherapy; Ketogenic diet; NRF1; NRF2.

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