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

Therapeutic 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 were constructed. Dysregulated mRNAs between ferroptosis-resistant and parental cell lines were identified. The expression of SOX13/SCAF1 was manipulated in GC cell lines where relevant biological and molecular analyses were performed. Molecular docking and computational screening were performed to screen potential inhibitors of SOX13. We showed 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, NADPH production and chemo- and immune-resistance. Zanamivir, reverted the ferroptosis-resistant phenotype via directly targeting SOX13 and promoting TRIM25-mediated ubiquitination and degradation of SOX13. Overall, SOX13/SCAF1 are important in ferroptosis-resistance, and targeting SOX13 with zanamivir has therapeutic potential. Overall design: To identify which genes binds directly to SOX13 and the genes with SOX13-bound transcription sites