TNFAIP3 suppresses lactylation-associated DNA damage repair and enhances chemosensitivity in ovarian cancer

Abstract Background Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies due to extensive metabolic plasticity and rapid development of platinum resistance. Lactylation, a lactate-derived post-translational modification, has emerged as a critical regulator linking tumor metabolism to cellular signaling. However, its role in OC remains poorly understood. Methods We integrated bulk transcriptomic analysis, single-cell RNA sequencing, machine-learning, clinical validation and functional experiments to characterize lactylation-associated programs in OC. TNFAIP3 expression and lactylation levels were evaluated using public datasets, immunoblotting, immunohistochemistry and multiplex immunofluorescence. Functional assays and xenograft models were performed to investigate the role of TNFAIP3 in tumor progression and chemoresistance. Results Global pan-Kla signals were significantly elevated in OC and correlated with advanced stage, metastasis, chemoresistance and poor prognosis. Single-cell analysis identified two lactylation-associated epithelial states, PFKP-C1 and CBX3-C2, representing metabolically adaptive and immune-interactive tumor programs respectively. An exploratory lactylation-related prognostic model was associated with survival differences and immune microenvironmental heterogeneity. Among the candidate genes, TNFAIP3 emerged as a functionally relevant candidate tumor suppressor and was markedly downregulated in OC, particularly in chemoresistant tumors, whereas high TNFAIP3 expression predicted favorable survival. Functionally, TNFAIP3 inhibited tumor progression while enhancing sensitivity to cisplatin and olaparib in vitro and potentiated cisplatin efficacy in vivo. Mechanistically, TNFAIP3 constrained LDHA-mediated lactate production, reduced NBS1-associated lactylation and was associated with attenuated DNA damage repair signaling. HDAC3 was further implicated as a functional mediator of TNFAIP3-associated NBS1 delactylation. Conclusions Our findings identify TNFAIP3 as a metabolic regulator that suppresses lactylation-associated DNA damage repair and enhances therapeutic sensitivity in ovarian cancer. These results support lactylation-associated signaling as a potential direction for further therapeutic investigation in ovarian cancer.