The p38α MAPK–MK2 axis drives chemotherapy-mediated nuclear actin remodeling to promote ovarian cancer progression

Nuclear F-actin facilitates DNA damage repair and contributes to cancer chemoresistance. However, the regulatory mechanisms controlling its dynamic polymerization in response to genotoxic stress remain poorly defined. A major barrier in nuclear actin research is the lack of tools for precise, high-throughput analysis. To systematically investigate nuclear F-actin assembly in DNA damage response, we developed a deep learning pipeline, named nFANet, for high-throughput detection and analysis of nuclear F-actin. Here, using ovarian cancer—a malignancy where chemoresistance is a major clinical obstacle—as a model, we showed that platinum-based chemotherapy robustly induces nuclear F-actin assembly. A subsequent kinome screening, in combination with the application of nFANet, identified the kinase p38α MAPK as a critical upstream regulator of platinum-induced nuclear F-actin assembly. Mechanistically, the p38α MAPK–MK2 signaling pathway promotes formin-mediated nuclear F-actin assembly in response to chemotherapy. Importantly, pharmacological inhibition or genetic knockout of the p38α MAPK–MK2 pathway sensitized ovarian cancer cells to platinum-based therapy. Our work uncovers a key mechanism governing nuclear actin remodeling under genotoxic stress and lays the foundation for identifying a patient subgroup likely to benefit from therapeutic targeting of this pathway.