Targeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer

• DOI: 10.1038/s41467-024-48307-z
• Publication Date: 2024-05-20T18:02:56Z
• Authors: Hui Yang; Qingqing Li; Xingxing Chen; Mingzhe Weng; Yakai Huang; Qiwen Chen; Xiaocen Liu; Haoyu Huang; Yanhuizhi Feng; Hanyu Zhou; Mengying Zhang; Weiya Pei; Xueqin Li; Qingsheng Fu; Liangyu Zhu; Yingying Wang; Xiang Kong; Kun Lv; Yan Zhang; Yangbai Sun; Mingzhe Ma
• Keywords: 0301 basic medicine; 0303 health sciences; Science; Ubiquitin-Protein Ligases; Q; Article; Mitochondria; Electron Transport; Molecular Docking Simulation; Gene Expression Regulation, Neoplastic; Mice; Stomach Neoplasms; Drug Resistance, Neoplasm; Cell Line, Tumor; Humans; Ferroptosis; Animals

AbstractTherapeutic resistance represents a bottleneck to treatment in advanced gastric cancer (GC). Ferroptosis is an iron-dependent form of non-apoptotic cell death and is associated with anti-cancer therapeutic efficacy. Further investigations are required to clarify the underlying mechanisms. Ferroptosis-resistant GC cell lines are constructed. Dysregulated mRNAs between ferroptosis-resistant and parental cell lines are identified. The expression of SOX13/SCAF1 is manipulated in GC cell lines where relevant biological and molecular analyses are performed. Molecular docking and computational screening are performed to screen potential inhibitors of SOX13. We show that SOX13 boosts protein remodeling of electron transport chain (ETC) complexes by directly transactivating SCAF1. This leads to increased supercomplexes (SCs) assembly, mitochondrial respiration, mitochondrial energetics and chemo- and immune-resistance. Zanamivir, reverts the ferroptosis-resistant phenotype via directly targeting SOX13 and promoting TRIM25-mediated ubiquitination and degradation of SOX13. Here we show, SOX13/SCAF1 are important in ferroptosis-resistance, and targeting SOX13 with zanamivir has therapeutic potential.