DUSP5 contributes to platinum resistance in ovarian cancer: single-cell discovery and functional validation

作者：Liu C, Li W, Liao T, Li Z, Huang G, Wang Q · 发表于：Frontiers in pharmacology · 年份：2026 · DOI：10.3389/fphar.2026.1842271 · 被引用次数：52

BACKGROUND: Platinum-based chemotherapy remains the cornerstone of ovarian cancer treatment, yet acquired resistance severely limits efficacy. Because platinum agents can also influence immunogenic cell death and tumor microenvironment (TME) remodeling, clarifying cellular pharmacological mechanisms of sensitivity and resistance within the ovarian cancer tumor ecosystem is important for understanding therapeutic failure. METHODS: We integrated single-cell RNA-seq from treatment-naïve and post-neoadjuvant chemotherapy ovarian tumors with bulk multi-omics cohorts to map epithelial tumor heterogeneity, transcriptional reprogramming, pathway activation, immune infiltration, and inferred cell-cell communication networks. DUSP5 was identified as a candidate regulator linked to stress-adaptive programs. Functional validation included qPCR, proliferation, migration, colony-formation, carboplatin dose-response, and xenograft assays following stable DUSP5 knockdown. RESULTS: Single-cell analysis revealed chemotherapy-associated epithelial states with enhanced stress, EMT, hypoxia, and inflammatory signatures. Elevated DUSP5 expression correlated with MAPK/JAK-STAT/TGF-β signaling, myeloid/stromal infiltration, and clinical outcome differences in independent cohorts. DUSP5 depletion suppressed proliferation and migration, amplified carboplatin-induced MAPK transcriptional responses and pro-apoptotic signaling (BAX/PUMA upregulation, BCL2 downregulation), reduced IC50 values in both OV...