FOXK2⁺ malignant epithelial cells promote platinum resistance via KANSL1-MOF-mediated redox sustaining mechanism in ovarian cancer

Platinum resistance remains a major obstacle in ovarian cancer therapy, yet the molecular programs that enable malignant cells to maintain redox balance and survive oxidative stress remain incompletely defined. Through integrated analyses of bulk RNA-seq, spatial transcriptomics, and single-cell datasets, we identify a distinct FOXK2-positive epithelial cancer population that is reproducibly detected across multiple patient cohorts. This FOXK2-high malignant cell state expands after chemotherapy, preferentially accumulates in recurrent and platinum-resistant tumors, and is consistently associated with inferior patient survival, indicating a potential role in therapy failure. Functional studies demonstrate that FOXK2 is required to maintain redox resilience in ovarian cancer cells. FOXK2 depletion increases intracellular ROS, disrupts mitochondrial respiration, and markedly sensitizes both in vitro cultures and in vivo xenografts to platinum treatment. These vulnerabilities are reversed by antioxidant supplementation, supporting a causal link between FOXK2 loss, ROS accumulation, and enhanced chemosensitivity. To uncover the molecular mechanism underlying FOXK2-mediated redox control, we performed immunoprecipitation-mass spectrometry and identified a previously unrecognized physical interaction between FOXK2 and the KANSL1-MOF chromatin-remodelling complex-an association not previously linked to redox biology, stress adaptation, or chemoresistance in ovarian cancer. FOXK2 leverages this newly defined interaction to recruit KANSL1-MOF to antioxidant gene promoters and enhancers, including SLC7A11, GCLC, and GPX2. This recruitment maintains H4K16 acetylation, preserves chromatin accessibility, and sustains transcriptional activation of key antioxidant programs. Loss of KANSL1 phenocopies FOXK2 depletion, leading to ROS accumulation and heightened platinum sensitivity, establishing KANSL1 as a critical FOXK2-dependent cofactor. Strikingly, this regulatory system is responsive to oxidative stress. Exposure to ROS increases FOXK2 and KANSL1 protein levels and enhances FOXK2-KANSL1 binding, creating a self-reinforcing, redox-sensitive positive feedback loop that sustains antioxidant capacity under therapeutic stress. Together, our findings reveal a therapy-selected FOXK2-positive malignant cell state and uncover a novel epigenetic FOXK2-KANSL1-MOF axis that couples chromatin remodeling to redox homeostasis and platinum resistance in ovarian cancer. Targeting FOXK2-high cellular states or disrupting their chromatin-associated cofactor network may offer a therapeutic strategy to overcome chemoresistance.