TARGETING TYPE-I PRMTS RESTORES PLATINUM SENSITIVITY IN OVARIAN CARCINOMA THROUGH MITOCHONDRIAL METABOLISM

Adaptive chemoresistance remains a critical barrier to effective ovarian cancer therapy, necessitating a deeper understanding of the cellular and metabolic changes that drive platinum resistance. Here, we dissect the interplay between platinum-induced genotoxic stress, type-I protein arginine methyltransferases–mediated post-translational modifications, and mitochondrial metabolic plasticity underpinning chemoresistance in EOC. We present an integrative multi-omics analysis of carboplatin-resistant A2780 ovarian cancer cells (A2780R) developed via stepwise drug adaptation, revealing pronounced mitochondrial and metabolic rewiring. A2780R cells display an 8.8-fold increase in carboplatin IC50 compared to parental A2780S cells and elevated mitochondrial respiratory capacity, and a hyperfused mitochondrial network, as quantified by 3D-skeleton imaging. Notably, pharmacological inhibition of Type-I protein arginine methyltransferases (PRMTs) with MS023 re-sensitizes A2780R cells to carboplatin, reducing IC50 by up to 56%, and abrogates the enhanced mitochondrial activity. MS023 treatment induces depolarization of the mitochondrial membrane, diminishes mitochondrial volume and network integrity, and triggers mitophagy. Proteomic and metabolomic analyses at steady state and upon PRMT inhibition revealed that A2780R cells adapt by favouring anabolic pathways, with notable upregulation of nucleotide and glutathione metabolism and increased amino acid catabolism. This metabolic rewiring is associated with elevated NADPH production from the pentose phosphate pathway, supporting enhanced glutathione-mediated redox buffering. MS023 disrupts these adaptations, depleting glutathione pools and precursor amino acids, reducing redox balance, and shifting central carbon metabolism. Isotope tracing confirms that A2780R cells channel serine-derived carbons into glutathione synthesis, a process blunted by Type-I PRMT inhibition. Mechanistic investigations indicate that R-methylation of mitochondrial proteins modulates biogenesis, metabolic flexibility, and oxidative stress buffering, establishing Type-I PRMTs as essential regulators of chemoresistance-associated metabolic shifts. Our findings position Type-I PRMT inhibition as a promising combinatorial approach to overcome platinum resistance by targeting maladaptive metabolic features in ovarian cancer cells. This study provides a comprehensive blueprint of the mitochondrial and metabolic phenotypes underpinning adaptive chemoresistance, highlighting the translational potential of metabolic vulnerabilities in the therapeutic sensitisation of resistant cancer phenotypes.