Hepatocellular carcinoma (HCC) is a lethal malignancy with approximately 860 000 new cases and 750 000 deaths annually worldwide.(p1) The International Agency for Research on Cancer (IARC) classifies circadian rhythm disruption as a Group 2A probable human carcinogen, highlighting its role as a risk factor for cancer.(p2) Epidemiological research involving shift workers, who often experience sleep disturbances, provides strong evidence linking circadian rhythm disruption to cancer, including HCC.(p3) Patients with HCC frequently exhibit circadian disturbances (e.g. insomnia and hypersomnia) that correlate with worsened prognosis and reduced quality of life.(p4) Recent evidence suggests a strong association between circadian rhythm disruption and HCC pathogenesis.(p5),(p6) Hence, it is of critical importance to elucidate the underlying mechanisms by which circadian rhythm disruption causes HCC.

The circadian rhythm system is modulated through a network of ‘endogenous oscillators’ that include: (i) the central suprachiasmatic nucleus (SCN) in the hypothalamus and (ii) the peripheral organs (e.g. heart, liver, and pancreas).(p7) These oscillators orchestrate physiological processes in a coordinated manner, including the sleep/wake cycle, feeding/fasting pattern, metabolic homeostasis, body temperature regulation, and endocrine function.(p8) Both the SCN and peripheral oscillators function via the transcription–translation feedback loop (TTFL), known as the molecular clock.(p9) Although the SCN synchronizes with the light–dark cycle primarily through the sensing of light exposure, the peripheral oscillators synchronize by receiving signals from the SCN.(p7) At the molecular level, two transcription factors, namely circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1), play a pivotal role in driving peripheral clock gene expression. This molecular machinery sustains circadian rhythmicity to ensure the incorporation of cellular and organ functions for maintaining systemic homeostasis.(p10),(p11),(p12),(p13)

Circadian rhythm disorders that are caused by disruptions in light/dark cycles and feeding/fasting patterns can cause conflict between central and peripheral circadian signals, resulting in the progression of chronic diseases and cancers.(p8),(p14) It has been reported that approximately 15% of circadian rhythm-associated transcripts are downregulated in HCC compared with normal hepatic tissue.(p15) Circadian disruption leads to clock gene dysregulation, resulting in sustained oncogenic pathway activation.(p16) However, the precise mechanisms through which circadian dysregulation affects HCC development and progression remain unclear.

In this review, we performed a systematic literature search in PubMed, focusing on representative and innovative studies and reviews published between 2016 and 2025. Our analysis focuses on the impact of circadian disruption on three key aspects: cell cycle regulation, metabolic reprogramming, and immune evasion. We also describe the functions of core clock proteins (CLOCK and BMAL1) and their downstream signaling molecules. In addition, we provide emerging approaches for HCC treatment.