Circadian disruption in hepatocellular carcinoma: Current findings and future directions of molecular mechanisms.

Hepatocellular carcinoma (HCC) is associated with multiple pathological processes. Accumulating evidence implicates circadian disruption in hepatocarcinogenesis, as it disrupts cell cycle regulation, metabolic homeostasis, and tumor immunity. Abnormal activation of clock proteins, particularly circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1), induces HCC cell proliferation, inhibits tumor apoptosis, and facilitates immune evasion, thereby leading to HCC development and progression. Circadian rhythm recovery by means of either pharmacological modulation of clock proteins or chronotherapy emerges as a promising strategy to suppress tumor growth and augment therapeutic efficacy. This review delineates the role of CLOCK and BMAL1 in HCC pathogenesis, discusses emerging circadian-based therapies, and highlights challenges for targeting circadian dysregulation to improve HCC treatment outcomes.