Metabolic molecular subtyping of ovarian cancer reveals the role of oleic acid-CD36 in facilitating cisplatin resistance

Current histopathological classification systems for ovarian cancer cannot adequately predict platinum chemotherapy response, hindering personalized therapeutic strategies. Here, through integrative analysis of multiple datasets from TCGA, ICGC and GEO databases, we stratify patients into metabolic associated chemotherapy-refractory and chemotherapy-sensitive types (MCRT, MCST for short) with distinct prognosis by 20 genes. Lipidomic profiling of ascites from patients with ovarian cancer further identifies oleic acid as a hallmark metabolite in MCRT cases. Oleic acid treatment facilitates the resistance to cisplatin in ovarian cancer cells and patient-derived organoids. Mechanistically, oleic acid activates and promotes nuclear translocation of YAP through CD36. Inhibition of SCD1-genetically or pharmacologically-synergizes with cisplatin in 26 patient-derived organoids and suppresses tumor growth in xenograft models. Our study proposes a new metabolic classification of ovarian cancer that can predict chemotherapy sensitivity. Moreover, it discovers the role of the oleic acid-CD36-YAP signaling axis in promoting cisplatin resistance. These findings shed light on how oleic acid facilitates the resistance to cisplatin in ovarian cancer and provide a potential therapeutic strategy for treating patients with ovarian cancer.