NFE2L1 promotes cisplatin resistance by attenuating ferroptosis through SLC27A2-mediated fatty acid metabolism in ovarian cancer

Abstract Approaches that promote ferroptosis have emerged as promising therapeutic strategies for chemotherapy-resistant cancers; however, the mechanisms regulating ferroptosis during acquired therapeutic resistance remain incompletely understood. Using RNA sequencing, we identified that Nuclear Factor Erythroid-2 Related Factor 1 (NFE2L1) is upregulated in cisplatin-resistant ovarian cancer (OC) cells and patient tissues, as well as in ferroptosis-resistant models. Genetic knockdown of NFE2L1 resensitized cells to cisplatin both in vitro and in vivo. Notably, this effect was largely reversed by ferroptosis inhibitors, which significantly rescued cell survival following NFE2L1 depletion under cisplatin treatment. Further experiments demonstrated that modulating NFE2L1 expression affects the response to ferroptosis inducers by regulating iron accumulation and lipid peroxidation. Mechanistically, NFE2L1 silencing increased the transcription of long-chain fatty acid transport protein 2 (SLC27A2/FATP2). Chromatin immunoprecipitation and dual-luciferase reporter assays showed that NFE2L1 bound directly to the SLC27A2 promoter, where it competitively inhibited the recruitment of the transcription factor SP1. As a key member of the long-chain acyl-CoA synthetase family, FATP2 promotes the uptake and activation of long-chain fatty acids, processes that have been implicated in the regulation of ferroptosis. Subsequent LC–MS-based lipidomic analysis revealed that NFE2L1 reprogrammed intracellular fatty acid metabolism, characterized by increased polyunsaturated fatty acid (PUFA) levels and decreased monounsaturated fatty acid (MUFA) levels within phosphatidylethanolamines (PEs), thereby increasing cellular susceptibility to ferroptosis. Consistent with these findings, supplementation with exogenous unsaturated fatty acids modulated NFE2L1-mediated ferroptosis sensitivity. Collectively, our findings reveal a novel NFE2L1/SLC27A2 axis that drives cisplatin resistance in OC by suppressing ferroptosis, and suggest a potential therapeutic strategy for treating cisplatin-resistant ovarian cancer.