{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T20:33:09Z","timestamp":1788208389284,"version":"build-2803163510"},"reference-count":35,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T00:00:00Z","timestamp":1754352000000},"content-version":"vor","delay-in-days":4,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death. Sorafenib, a multikinase inhibitor, has been approved as a first\u2010line systemic therapeutic for HCC patients based on the results of two large clinical trials, in which sorafenib significantly increased life expectancy of patients with Child Pugh A advanced stage of liver cancer, no matter which races they were or whether being infected with hepatitis B or C virus; however, its efficacy is compromised by the resistance of the tumor cells. By using integrative bioinformatics analysis, we identified ferroptosis as a candidate to modulate sorafenib\u2010resistant HCC. Ferroptosis is a novel, iron\u2010dependent, non\u2010apoptotic regulated cell death with characteristics of impaired lipid peroxide repair, redox active iron, and the oxidation of polyunsaturated fatty acids. Here, glutathione peroxidase 4 (GPX4) was further identified as a favorable prognostic factor in cancer survival by analyzing data repositories. Compared to the parental human HCC Huh7 cells, lower expression of GPX4, dysregulated iron homeostasis, and higher expression of acyl\u2010CoA synthetase long\u2010chain family member 4 were observed in sorafenib\u2010resistant Huh7R cells, and the Huh7R cells exhibited higher sensitivity to ferroptosis induction exerted by RSL3, a GPX4 inhibitor. The RSL3\u2010induced ferroptosis was attenuated by lysosomal blocker bafilomycin A1, indicating that lysosomal degradation of ferritin may confer sensitivity to GPX4\u2010inactivation\u2010induced ferroptosis by providing accessible iron. Taken together, our findings demonstrate that GPX4\u2010inactivation\u2010induced ferroptosis is a promising and effective treatment option capable of overcoming sorafenib resistance in liver cancer, and our novel gene expression\u2010screening platform via integrated analysis of differentially expressed genes and pathways allows efficient identification of therapeutic strategies.<\/jats:p>","DOI":"10.1002\/jcp.70078","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T17:50:02Z","timestamp":1754416202000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Targeting GPX4 to Overcome Sorafenib Resistance of Human Hepatocellular Carcinoma by Inducing Ferroptosis"],"prefix":"10.1002","volume":"240","author":[{"given":"Han\u2010Hsuan","family":"Tang","sequence":"first","affiliation":[{"name":"Graduate Program of Nutrition Science, School of Life Science National Taiwan Normal University 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