Hepatocellular Carcinoma Around the Clock

The dramatic shift in human behavior from hunter-gatherer to modern lifestyles has led to a systematic disruption of the human circadian cycle. Contributors include night-shift work, jet lag, and less intuitive but widespread factors, such as exposure to artificial light at night and irregular eating schedules. Circadian disruption is classified as a Group 2A carcinogen by the International Agency for Research on Cancer (IARC). Hepatocellular carcinoma (HCC) is the third most deadly cancer worldwide, with a rising prevalence in Western countries, largely driven by increasing rates of obesity and steatotic liver disease-associated hepatocarcinogenesis. Emerging evidence suggests that circadian disruption plays a significant role in HCC pathogenesis. Several genes involved in metabolism, cell survival, and immunosurveillance are under the control of circadian rhythms. Experimental preclinical data and epidemiological studies have indicated a strong association between circadian disruption and HCC development. Moreover, molecular signatures related to circadian regulation appear to accurately predict the prognosis of patients with HCC. The concept of chronotherapy is also gaining interest, with studies suggesting improved immunotherapy effectiveness when immune checkpoint inhibitors are administered in the morning. This review summarizes the current literature on the impact of circadian disruption on HCC pathogenesis, prognosis, and treatment.