# Hepatocellular Carcinoma Around the Clock

## TL;DR

Disrupted circadian rhythms contribute to liver cancer development and treatment outcomes, suggesting lifestyle and timed therapies could help prevent and treat the disease.

## Contribution

This review highlights the role of circadian disruption in HCC and proposes chronotherapy as a potential treatment strategy.

## Key findings

- Circadian disruption is linked to HCC through metabolic and oncogenic pathways.
- Molecular circadian signatures predict HCC prognosis.
- Chronotherapy improves immunotherapy effectiveness when timed appropriately.

## Abstract

Lifestyle-related circadian rhythm disruptions favor the development of hepatocellular carcinoma (HCC) both indirectly (by promoting precursor conditions such as metabolic dysfunction-associated liver disease and liver cirrhosis) and directly through intrinsic oncogenic effects. Population-level interventions that promote circadian realignment may help prevent the increasing incidence of HCC. Assessing circadian disruption could also help determine the prognosis of individual patients and their potential responses to therapy. Therapy strategies should incorporate chronotherapy principles, aiming not only to realign patient’s circadian cycles but also to optimize the timing of therapeutic delivery according to circadian variations in pharmacokinetics and pharmacodynamics to improve efficacy.

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.