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Review Open Access

Circadian clock genes: Their influence on liver metabolism, disease development and treatment (Review)

  • Authors:
    • Junmin Wang
    • Mengxing Cao
    • Shen Li
    • Wen Pei
    • Jing Li
    • Zhen Wang
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China, Integrated Chinese Medicine Treatment Department, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China, Department of Nursing, The People's Hospital of Yubei District of Chongqing, Chongqing 401120, P.R. China, Department of Traditional Chinese Medicine, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, P.R. China
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 3
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    Published online on: October 14, 2025
       https://doi.org/10.3892/mmr.2025.13713
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Abstract

The present review comprehensively discusses the impact of circadian clock genes on hepatic metabolism, liver disease progression and therapeutic strategies. The circadian rhythm, as a fundamental regulatory system, governs metabolic, immune and endocrine processes through an integrated central‑peripheral network. Disruption of this rhythm plays a pivotal role in the pathogenesis of various liver diseases, including non‑alcoholic fatty liver disease, alcoholic liver disease, liver fibrosis and hepatocellular carcinoma. Key circadian regulators, including circadian locomotor output cycles kaput, brain and muscle ARNT‑like protein 1, period circadian regulator 1/2 and cryptochrome 1/2 modulate critical pathways, including lipid and glucose metabolism, bile acid synthesis, inflammatory responses and cellular repair, thereby contributing to the progression of liver disease. Chronotherapeutic approaches, such as targeted pharmacological treatments, time‑restricted feeding and light therapy, show promising clinical potential. However, further research is essential to clarify the underlying mechanisms and enable clinical application. By integrating foundational studies with clinical evidence, the present review provides a framework for chrono‑precision medicine in hepatology, while identifying current challenges and proposing strategies to accelerate the development and clinical implementation of circadian rhythm‑based therapies for liver disease.
View Figures

Figure 1

Regulation process of the central and
peripheral biological clocks. The circadian system undergoes daily
regulation by natural light, food intake and other external cues.
Light serves as the principal zeitgeber, transmitting signals via
the retina and retinohypothalamic tract to the suprachiasmatic
nucleus, thereby resetting the central pacemaker. While the master
clock resides within the hypothalamic center, peripheral
oscillators exist in the liver, kidneys, adipose tissue, pancreas
and heart, all synchronized by the master clock. Bmal1, brain and
muscle ARNT-like protein 1; Clock, circadian locomotor output
cycles kaput; Cry, cryptochrome; Per, period circadian
regulator.

Figure 2

Schematic diagram of the liver
circadian clock. The liver clock is composed of three parts: The
input pathway, central oscillator and output pathway. The central
oscillator comprises two regulatory loops: The core loop and the
stabilizing loop. In the core loop, Bmal1 and Clock form
heterodimers in the cytoplasm and translocate to the nucleus, where
they bind to E-box sequences in the promoters of target
genes Per and Cry, initiating their transcription. As
Cry protein accumulates in the cytosol, it combines with Per
protein to form a stable complex that re-enters the nucleus and
binds to the Bmal1-Clock heterodimer, inhibiting its
transcriptional activity and reducing Per and Cry protein
synthesis. This cycle forms the oscillatory expression of circadian
clock molecules. The stabilizing loop regulates Bmal1 expression.
Bmal1-Clock dimers bind to E-box elements in the promoters
of the nuclear receptor genes Rev-erbα and RORα,
activating the transcription of Rev-erbα and RORα,
which compete for the RRE site of the Bmal1 promoter: RORα
activates Bmal1 expression, while Rev-erbα inhibits it, thereby
maintaining the stability of the circadian rhythm (32–34).
Bmal1, brain and muscle ARNT-like protein 1; Clock, circadian
locomotor output cycles kaput; Cry, cryptochrome; P, phosphor; Per,
period circadian regulator; Rev-erbα, reverse erythroblastosis
virus α; RORα, retinoic acid receptor-related orphan receptor
α.

Figure 3

Physiology and potential disease
associations of the liver circadian clock. The hepatic circadian
clock can be disrupted or phase-shifted by various factors,
including hormones, nutrients and environmental chemicals. These
input signals reset or alter the molecular clock, impacting
downstream outputs such as nutrient and xenobiotic metabolism, as
well as the cell cycle. Impairment of the circadian clock may
contribute to the development and progression of chronic liver
disease. Bmal1, brain and muscle ARNT-like protein 1; Clock,
circadian locomotor output cycles kaput; Cry, cryptochrome; Per,
period circadian regulator.

Figure 4

Impact of circadian clock disturbance
on liver diseases. The liver performs multiple critical functions,
including metabolism, detoxification, immune defense, secretion and
synthesis. Disruption in the expression of circadian clock genes
within the liver can impair its normal physiological functions,
contributing to the pathogenesis of liver diseases, including
NAFLD, ALD, LF and HCC. ALD, alcohol-related liver disease; Bmal1,
brain and muscle ARNT-like protein 1; Clock, circadian locomotor
output cycles kaput; Cry, cryptochrome; HCC, hepatocellular
carcinoma; LF, liver fibrosis; NAFLD, non-alcoholic fatty liver
disease; Per, period circadian regulator; PPAR, peroxisome
proliferator-activated receptor; Rev-erbα, reverse erythroblastosis
virus α; RORa, retinoic acid receptor-related orphan receptor
α.
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Copy and paste a formatted citation
Spandidos Publications style
Wang J, Cao M, Li S, Pei W, Li J and Wang Z: Circadian clock genes: Their influence on liver metabolism, disease development and treatment (Review). Mol Med Rep 33: 3, 2026.
APA
Wang, J., Cao, M., Li, S., Pei, W., Li, J., & Wang, Z. (2026). Circadian clock genes: Their influence on liver metabolism, disease development and treatment (Review). Molecular Medicine Reports, 33, 3. https://doi.org/10.3892/mmr.2025.13713
MLA
Wang, J., Cao, M., Li, S., Pei, W., Li, J., Wang, Z."Circadian clock genes: Their influence on liver metabolism, disease development and treatment (Review)". Molecular Medicine Reports 33.1 (2026): 3.
Chicago
Wang, J., Cao, M., Li, S., Pei, W., Li, J., Wang, Z."Circadian clock genes: Their influence on liver metabolism, disease development and treatment (Review)". Molecular Medicine Reports 33, no. 1 (2026): 3. https://doi.org/10.3892/mmr.2025.13713
Copy and paste a formatted citation
x
Spandidos Publications style
Wang J, Cao M, Li S, Pei W, Li J and Wang Z: Circadian clock genes: Their influence on liver metabolism, disease development and treatment (Review). Mol Med Rep 33: 3, 2026.
APA
Wang, J., Cao, M., Li, S., Pei, W., Li, J., & Wang, Z. (2026). Circadian clock genes: Their influence on liver metabolism, disease development and treatment (Review). Molecular Medicine Reports, 33, 3. https://doi.org/10.3892/mmr.2025.13713
MLA
Wang, J., Cao, M., Li, S., Pei, W., Li, J., Wang, Z."Circadian clock genes: Their influence on liver metabolism, disease development and treatment (Review)". Molecular Medicine Reports 33.1 (2026): 3.
Chicago
Wang, J., Cao, M., Li, S., Pei, W., Li, J., Wang, Z."Circadian clock genes: Their influence on liver metabolism, disease development and treatment (Review)". Molecular Medicine Reports 33, no. 1 (2026): 3. https://doi.org/10.3892/mmr.2025.13713
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