Integrated multi-omics, spatial transcriptomics, and functional studies implicate MDK as a mediator of cisplatin-response phenotypes in ovarian cancer

Abstract Platinum resistance remains a central barrier to durable disease control in ovarian cancer. In this study, we integrated an ovarian cancer susceptibility GWAS, multi-omics profiling (CPTAC/TCGA), and spatial-single-cell transcriptomics to identify novel therapeutic targets. Cross-platform prioritization nominated midkine (MDK) as a prominent candidate associated with platinum-response phenotypes. Mapping of MDK via scRNA-seq and spatial transcriptomics localized its expression primarily to tumor-associated compartments, suggesting a critical role in microenvironmental remodeling. Clinically, in an expanded retrospective cohort of 138 patients, high MDK expression demonstrated a robust adjusted association with platinum resistance and poor overall survival, a finding further validated by propensity-score matching. Functionally, MDK depletion significantly attenuated malignant phenotypes and sensitized ovarian cancer cells to cisplatin in vitro , while strongly potentiating cisplatin-induced tumor suppression in in vivo xenograft models. Mechanistically, complementary in silico virtual perturbation analyses predicted a regulatory link between MDK and survival signaling networks. This was experimentally corroborated by bidirectional pharmacological rescue assays, which revealed that MDK drives cisplatin resistance primarily through the PI3K/AKT signaling axis, subsequently regulating ABCB1, SOX2, and BAX expression. Together, these findings support MDK as a clinically relevant mediator of AKT-dependent platinum resistance, highlighting its potential utility for future prognostic and targeted therapeutic strategies.