Targeting the PHB2–ACSL3 Lipid‐Remodeling Axis Overcomes Cisplatin Resistance by Restoring Ferroptosis in Gastric Cancer
ABSTRACT Platinum‐based chemotherapy resistance remains a major obstacle in gastric cancer (GC) treatment. Through integrated transcriptomic profiling of cisplatin‐resistant xenografts and pharmacogenomic interrogation of the NCI‐60 dataset, we identified Prohibitin‐2 (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‐metabolic enzyme ACSL3 through a defined AMP‐binding–domain 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‐resistant state. Structure‐based virtual screening of an FDA‐approved drug library nominated the CXCR4 antagonist Mavorixafor as a potent inhibitor of the PHB2–ACSL3 interaction. Mavorixafor disrupted lipid remodeling, restored ferroptosis susceptibility, and resensitized cisplatin‐resistant GC in cell line–derived xenografts (CDOs) and patient‐derived organoids (PDOs). The therapeutic effect was abrogated by the ferroptosis inhibitor Liproxstatin‐1, confirming ferroptosis dependence. Collectively, our findings define a PHB2–ACSL3 lipid‐metabolic axis that drives ferroptosis escape and identify Mavorixafor repurposing as an immediately translatable strategy to overcome cisplatin resistance in treatment‐refractory GC.