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Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, and emerging evidence implicates circadian rhythm disruption in its pathogenesis. Here, we identified the core circadian gene  Cryptochrome1  ( Cry1 ) as a potential tumor suppressor in HCC. Clinical analysis revealed that low  Cry1  expression correlated with poor prognosis, showing a median survival of 36 vs 47 months, and  Cry1  expression was significantly reduced in HCC cell lines (0.6-fold in SMMC-7721 vs LO2). Functional studies demonstrated that  Cry1  overexpression reduced proliferation by 30% with more cells in the G1 phase, as well as inhibited migration/invasion, while  Cry1  knockdown increased proliferation by 50% with less cells in the G1 phase and increased migration/invasion. Finally, we found  Cry1  depletion downregulated pro-apoptotic BAX and upregulated anti-apoptotic BCL2, while  Cry1  overexpression produced the opposite effects, suggesting its role in apoptosis via the BCL2/BAX-mediated apoptosis pathway. These findings indicate that  Cry1  acts as a tumor suppressor in HCC, providing insights into the circadian dysfunction-cancer pathogenesis connection and its potential as a diagnostic biomarker and therapeutic target requires further verification through preclinical and clinical investigations in the future.

Circadian gene Cry1 inhibits the tumorigenicity of hepatocellular carcinoma by the BAX/BCL2-mediated apoptosis pathway