Background: Platinum-based chemotherapy is the frontline treatment for high-grade serous ovarian cancer (HGSOC); however, the development of therapy resistance greatly limits clinical response. Increasing evidence suggests that platinum agent-driven metabolic programming, particularly within redox-associated pathways, may contribute to chemoresistance. Methods: A syngeneic pair of patient-derived HGSOC cell lines representing cisplatin-sensitive (SE) and cisplatin-resistant (CR) states were evaluated using a multi-omics approach. Differential metabolite abundance and gene expression were assessed, followed by gene set and pathway enrichment analyses to identify coordinated metabolic shifts. In silico analysis of an additional sensitive and resistant HGSOC cell line validated the glutathione pathway upregulation seen in the patient-derived model. The functional contribution of the glutathione pathway on cisplatin resistance was evaluated following glutathione inhibition. Results: Chronic cisplatin exposure induced extensive metabolic rewiring in CR cells, characterized by enrichment of glutathione metabolism at both the metabolite and gene levels. Increased reduced glutathione was observed alongside upregulation of key enzymes involved in its de novo biosynthesis, recycling, and utilization, consistent with enhanced detoxification capacity relating to cisplatin-induced oxidative stress. Additionally, taurine was highly enriched, further highlighting a metabolic shift towards enhanced antioxidant mechanisms. CR cells also demonstrated an increase in NADPH-generating pathways, including amino acid metabolism and fatty acid β oxidation, to support redox balance and biosynthetic demands of increased glutathione metabolism. Transcriptional remodeling of the γ-glutamyl cycle further indicated a shift toward increased glutathione turnover, suggesting that the coordinated changes seen may define a metabolic state enhanced in oxidative stress tolerance and therapeutic resistance. These transcriptional changes were also seen in another model of platinum sensitivity/resistance, indicating a conserved response associated with platinum-induced resistance. Finally, concurrent cisplatin treatment and glutathione inhibition significantly increased sensitivity within the CR cells. Conclusions: These findings suggest that cisplatin-resistant cells, previously exposed to a platinum-based agent, may undergo distinct metabolic rewiring towards antioxidant pathways to survive chronic chemotherapeutic stress. Targeting components of these systems may represent a viable strategy to overcome platinum resistance and improve therapeutic outcomes.
Conant et al. (Mon,) studied this question.