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However, emerging evidence indicates that hepatocellular carcinoma (HCC) frequently exhibits resistance to ferroptosis induction, while the underlying molecular mechanism is poorly understood. Here, we found that aldo\u2010keto reductase family 1 member C3 (AKR1C3), a protein highly expressed in ferroptosis\u2010resistant HCC cells, negatively regulates ferroptosis in an enzyme\u2010independent manner. Mechanistically, AKR1C3 promotes ubiquitin\u2010proteasomal degradation of the transferrin receptor (TFRC), which is indispensable for cellular iron uptake. AKR1C3 knockdown restores TFRC expression, increases the level of labile iron pool, and sensitizes HCC cells to ferroptosis. Furthermore, AKR1C3 acts as a scaffolding protein to promote the degradation of TFRC and reduce iron uptake by promoting nuclear export of Beta\u2010transducin repeats\u2010containing proteins (\u03b2\u2010TrCP) and its binding to TFRC. Notably, AKR1C3 is upregulated in NRF2\u2010driven sorafenib\u2010resistant HCC, and its inhibition reversed ferroptosis and sorafenib resistance. Our work uncovers AKR1C3 suppresses ferroptosis in HCC by promoting \u03b2\u2010TrCP\u2010mediated TFRC degradation, positioning AKR1C3 as a promising therapeutic target to enhance ferroptosis\u2010based anticancer strategies.<\/jats:p>","DOI":"10.1111\/cas.70403","type":"journal-article","created":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T07:06:31Z","timestamp":1777705591000},"page":"1867-1882","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>AKR1C3<\/scp>\n                    Binds \u03b2\u2010Trcp to Promote the Degradation of\n                    <scp>TFRC<\/scp>\n                    to Protect Hepatocellular Carcinoma From Ferroptosis"],"prefix":"10.1111","volume":"117","author":[{"given":"Lei","family":"Qi","sequence":"first","affiliation":[{"name":"School of Basic Medicine and Clinical Pharmacy China Pharmaceutical University  Nanjing Jiangsu 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