The circadian gene CHRONO drives hepatocellular carcinoma proliferation via G1/S cell cycle transition

Clock genes are essential for physiological homeostasis, and their dysregulation is closely linked to cancer malignancy. While inhibiting aberrantly expressed clock genes can suppress cancer cell proliferation, targeting core clock components often disrupts the fundamental circadian oscillatory system, posing potential risks to systemic physiology. CHRONO, a recently identified clock gene, functions as a unique transcriptional repressor whose deletion does not impair circadian oscillations, suggesting that it may represent a safer therapeutic target. In this study, we elucidated the clinical and pathological significance of CHRONO in cancer. Pan-cancer database analyses revealed that CHRONO expression is elevated across multiple malignancies; notably, in hepatocellular carcinoma (HCC), high CHRONO expression significantly correlates with poorer prognosis. Consistent with these findings, functional assays in human and murine hepatocarcinoma cells demonstrated that Chrono knockdown markedly inhibits cell proliferation. Mechanistically, suppression of CHRONO induced G1-phase arrest by decreasing the protein expression of key cell cycle regulators, including cyclin D and cyclin E. Collectively, our findings provide the first functional evidence that CHRONO acts as a pro-proliferative regulator in HCC, suggesting that modulation of CHRONO may suppress tumor growth while minimizing disruption of the core circadian oscillator.