STAT5A-RNF8 signaling regulates homologous recombination repair and cisplatin responsiveness in cervical cancer

Cisplatin resistance remains a major limitation in the treatment of cervical cancer, with enhanced DNA damage repair contributing to reduced therapeutic sensitivity. The role of STAT5A in coordinating DNA double-strand break repair under therapeutic stress remains unclear. Here, we investigated the role of STAT5A in cisplatin responsiveness using clinical tissue analysis, CRISPR/Cas9-based genetic models, DNA repair assays, and xenograft models. STAT5A depletion sensitized cervical cancer cells to cisplatin, whereas STAT5A overexpression reduced cisplatin sensitivity. Mechanistically, STAT5A showed increased spatial association with γH2AX-positive nuclear regions following cisplatin exposure and transcriptionally promoted RNF8 expression. STAT5A enhanced HR-associated repair through an RNF8-mediated mechanism, as supported by reciprocal genetic experiments and residual DNA damage analysis. STAT5A loss was accompanied by reduced ATM/CHK2 activation, decreased expression of MRN complex components, RNF8 and RAD51, and increased persistence of cisplatin-associated DNA damage. Importantly, pharmacological inhibition of STAT5 reduced RNF8 expression, increased DNA damage, and enhanced the antitumor activity of cisplatin in cellular and xenograft models. Together, these findings identify STAT5A-RNF8 signaling as a regulator of HR-associated DNA repair and cisplatin responsiveness in cervical cancer and support further evaluation of this pathway as a therapeutic target.