Srinivasa Samanmitha, Charmanna Shuchi Odiyanda, Nayak Rachana Rajesh, Karunakara Shreyas Hulusemane, Santhekadur Prasanna Kumar
Centre of Excellence in Molecular Biology and Regenerative Medicine, Department of Biochemistry, JSS Medical College, Mysuru, Karnataka, India.
Hum Cell. 2025 Sep 16;38(6):160. doi: 10.1007/s13577-025-01288-7.
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.
肝脏是最大的内部器官。肝脏具有多种关键功能，包括新陈代谢、血清蛋白合成、排泄、解毒以及维持身体内环境稳态所必需的各种生理过程。其独特的再生能力有助于肝脏在受损后完全自我修复。这个过程涉及所有肝细胞，无论有无干细胞的参与。已知肝脏的功能受昼夜节律调节，昼夜节律包括进食 - 禁食周期以及作为主时钟起调节作用的视交叉上核（SCN）的维持。肝脏的正常功能对于整体内环境稳态的维持至关重要，因为它作为一个外周时钟，这表明SCN与肝脏之间存在潜在联系。这些昼夜节律的异常与各种慢性肝病有关，如代谢功能障碍相关脂肪性肝病（MASLD），其可导致肝细胞癌（HCC）。这篇综述探讨了昼夜节律在肝脏功能中的重要性，重点关注褪黑素和核受体如维甲酸受体相关孤儿受体α（RORα）的作用，RORα是一种已知的对维持这些节律至关重要的褪黑素受体，这些节律可影响包括免疫系统功能、细胞生长和分化在内的生物学功能。此外，RORα被确定为炎症的关键调节因子之一，并作为一种潜在的肿瘤抑制因子，特别是在HCC的背景下。这篇综述探讨了RORα、褪黑素和昼夜节律之间的相互作用，并讨论了相关基础，这些基础为深入了解昼夜节律紊乱在HCC发展中的作用以及针对昼夜节律调节的新型治疗策略以减轻HCC提供了见解。
