NAD(H)-dependent corepressor CTBP1 integrates metabolic signals to drive oncogenic programs.

C-terminal binding protein 1 (CTBP1) is an NAD(H)-dependent transcriptional corepressor that links cellular metabolic state to chromatin-based gene regulation. Since its initial identification, CTBP1 has been implicated in a broad range of developmental and pathological processes, including cancer. Increasing evidence suggests that CTBP1 integrates redox cues, epigenetic repression, and transcriptional networks controlling epithelial plasticity, survival, DNA damage responses, and therapy resistance across multiple malignancies. In this review, we critically examine the current literature on CTBP1 structure, regulation, and function, with a particular focus on cancer biology. We synthesize findings from experimental studies that support CTBP1 as an oncogenic driver in specific tumor contexts, while explicitly highlighting settings in which evidence remains indirect, incomplete, or confined to locus-associated noncoding RNAs rather than CTBP1 protein itself. We further discuss the constraints and uncertainties surrounding CTBP1-directed therapeutic strategies, including incomplete mechanistic validation, context-dependent functions, and potential on-target toxicity arising from CTBP1's roles in normal metabolic and transcriptional homeostasis. Overall, this review positions CTBP1 as a context-dependent transcriptional integrator whose pathological functions are shaped by metabolic stress and epigenetic regulation, while emphasizing unresolved questions and experimental gaps that must be addressed before CTBP1 can be reliably evaluated as a therapeutic target.