The Role of miRNAs in Regulating Cellular Senescence: A Potential Strategy for Overcoming Drug Resistance in Ovarian Cancer

Ovarian cancer remains one of the most lethal gynecological malignancies, largely due to late diagnosis and the frequent development of resistance to platinum-based chemotherapy and taxanes. Increasing evidence implicates microRNAs as key regulators of drug response through their control of DNA damage response and repair, apoptosis, epithelial–mesenchymal transition, and therapy-induced cellular senescence. Senescence is a double-edged process characterized by irreversible cell-cycle arrest and the secretion of pro-inflammatory factors collectively known as the senescence-associated secretory phenotype, which may suppress tumor growth but also promote chemoresistance and disease recurrence. This review summarizes current evidence on microRNA (miRNA)-mediated regulation of therapy-induced cellular senescence and its role in drug resistance in ovarian cancer. We integrate data from mechanistic studies, preclinical models, and clinical observations, focusing on senescence-associated miRNAs and their regulatory networks. miRNAs including miR-34a, miR-21, miR-146a, miR-200c, miR-506, and miR-433 regulate key senescence pathways, notably p53/p21 and p16-RB signaling, and modulate the senescence-associated secretory phenotype by controlling inflammatory mediators, extracellular matrix remodeling, and angiogenic factors. Several of these miRNAs are also associated with resistance to platinum-based chemotherapy, taxanes, poly ADP-ribose polymerase (PARP) inhibitors, and immunotherapies through effects on PI3K/AKT and Hippo signaling pathways, as well as DNA repair mechanisms. Emerging therapeutic strategies aim to modulate or eliminate senescent cells using miRNA mimics, inhibitors, or gene-editing approaches, including nanoparticle-based delivery systems. Although preclinical studies suggest that these approaches may restore chemosensitivity, clinical translation remains limited by delivery challenges, off-target effects, and the context-dependent role of senescence. Targeting miRNA-senescence regulatory axes may represent a strategy for addressing drug resistance in ovarian cancer and warrants further investigation as part of combination treatment strategies.