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Through integrated transcriptomic profiling of cisplatin\u2010resistant xenografts and pharmacogenomic interrogation of the NCI\u201060 dataset, we identified Prohibitin\u20102 (PHB2) as a previously unrecognized determinant of chemoresistance. PHB2 was consistently upregulated in resistant tumors and associated with poor clinical outcomes. Mechanistically, PHB2 binds the lipid\u2010metabolic enzyme ACSL3 through a defined AMP\u2010binding\u2013domain interface (residues W244\/H254\/E260), enhancing ACSL3 activity to promote monounsaturated fatty acid incorporation into phospholipids. This phospholipid remodeling suppresses lipid peroxidation and establishes a ferroptosis\u2010resistant state. Structure\u2010based virtual screening of an FDA\u2010approved drug library nominated the CXCR4 antagonist Mavorixafor as a potent inhibitor of the PHB2\u2013ACSL3 interaction. Mavorixafor disrupted lipid remodeling, restored ferroptosis susceptibility, and resensitized cisplatin\u2010resistant GC in cell line\u2013derived xenografts (CDOs) and patient\u2010derived organoids (PDOs). The therapeutic effect was abrogated by the ferroptosis inhibitor Liproxstatin\u20101, confirming ferroptosis dependence. Collectively, our findings define a PHB2\u2013ACSL3 lipid\u2010metabolic axis that drives ferroptosis escape and identify Mavorixafor repurposing as an immediately translatable strategy to overcome cisplatin resistance in treatment\u2010refractory GC.<\/jats:p>","DOI":"10.1002\/advs.77350","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T15:49:56Z","timestamp":1787327396000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the PHB2\u2013ACSL3 Lipid\u2010Remodeling Axis Overcomes Cisplatin Resistance by Restoring Ferroptosis in Gastric Cancer"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2861-6304","authenticated-orcid":false,"given":"Liang","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Immunology School of Basic Medical Sciences Anhui Medical University  Hefei China"},{"name":"State Key Laboratory of Metabolic 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