Restoration of miR-188-5p Reverses PARP Inhibitor Resistance in High-Grade Serous Ovarian Cancer via Apoptosis Induction and DNA Repair Suppression

High-grade serous ovarian cancer (HGSOC) represents the most aggressive subtype of epithelial ovarian cancer and remains a leading cause of gynecologic cancer mortality. Although initial responses to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi) are often favorable, the eventual development of drug resistance severely limits long-term therapeutic efficacy. Emerging evidence highlights the role of microRNAs (miRNAs) in mediating treatment resistance through the regulation of key cellular processes, including DNA repair, apoptosis, and epithelial-mesenchymal transition (EMT). In this study, we performed miRNA expression profiling on formalin-fixed paraffin-embedded (FFPE) tumor samples from HGSOC patients and validated our findings in established olaparib-resistant HGSOC cell lines. Among the differentially expressed miRNAs, miR-188-5p was consistently downregulated in resistant tumors and in vitro cell models. Functional analyses demonstrated that ectopic expression of miR-188-5p restored sensitivity to olaparib, significantly increasing apoptosis and activating DNA damage response pathways, as indicated by elevated levels of phosphorylated ATR (p-ATR) and γH2AX. Furthermore, miR-188-5p over-expression induced a mesenchymal-to-epithelial transition, evidenced by increased E-cadherin, decreased N-cadherin, and reduced cellular migration. Notably, in patient-derived ex vivo tumor cultures, olaparib-resistant samples exhibited low endogenous miR-188-5p levels, and transfection with a miR-188-5p mimic significantly enhanced drug responsiveness. These findings identify miR-188-5p as a key modulator of PARPi resistance and a promising therapeutic target to enhance olaparib efficacy in HGSOC.