Melatonin, ROR-α and circadian rhythm in liver

The liver is the largest internal organ. Several critical functions are attributed to the liver which include metabolism, synthesis of serum proteins, excretion, detoxification, and various physiological processes essential for maintaining body homeostasis. Its unique regenerative capacity helps the liver to restore itself fully after injury. This process involves all hepatocytes with or without the involvement of stem cells. The function of the liver is known to be regulated by circadian rhythm, which includes feeding-fasting cycles and the maintenance of the suprachiasmatic nucleus (SCN) that regulates as a master clock. The normal functioning of the liver is critical to the overall maintenance of homeostasis as it serves as a peripheral clock, suggesting a potential link between the SCN and liver. Aberrations in these circadian rhythms have been linked to various chronic hepatic diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD), which can lead to Hepatocellular carcinoma (HCC). This mini review explores the significance of circadian rhythm in liver function, with a focus on the role of melatonin and nuclear receptors such as Retinoic acid receptor-related orphan receptor-alpha (RORα), which is a known melatonin receptor critical to sustaining these rhythms that can influence biological functions, including immune system functioning, cell growth, and differentiation. Further, RORα is identified as one of the key regulators of inflammation and acts as a potential tumor suppressor, particularly in the context of HCC. This review explores the interplay between RORα, melatonin, and circadian rhythm and discusses the underpinnings that offer insights into the role of circadian rhythm disruption in HCC development and novel therapeutic strategies targeting circadian rhythm modulations to mitigate HCC.