Tu HS, Chen ML, Hong J, He L. Chrono-metabolic regulation of hepatic fibrosis via NR1D1-mediated hepatic stellate cell activation. World J Hepatol 2026; 18(8): 118194 [DOI: 10.4254/wjh.118194]
Corresponding Author of This Article
Ling He, PhD, Professor, Department of Gastroenterology, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, No. 445 Bayi Avenue, Nanchang 330006, Jiangxi Province, China. heling118@126.com
Research Domain of This Article
Gastroenterology & Hepatology
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review-article
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Tu HS, Chen ML, Hong J, He L. Chrono-metabolic regulation of hepatic fibrosis via NR1D1-mediated hepatic stellate cell activation. World J Hepatol 2026; 18(8): 118194 [DOI: 10.4254/wjh.118194]
World J Hepatol. Aug 27, 2026; 18(8): 118194 Published online Aug 27, 2026. doi: 10.4254/wjh.118194
Chrono-metabolic regulation of hepatic fibrosis via NR1D1-mediated hepatic stellate cell activation
Hou-Shu Tu, Meng-Lin Chen, Jing Hong, Ling He
Hou-Shu Tu, Meng-Lin Chen, Ling He, Department of Clinical Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, Jiangxi Province, China
Jing Hong, Department of Otorhinolaryngology, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, Jiangxi Province, China
Ling He, Department of Gastroenterology, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, Jiangxi Province, China
Author contributions: Tu HS and Chen ML conceived and drafted the manuscript; Hong J provided critical content review; He L supervised and revised the work. All authors approved the final manuscript.
Conflict-of-interest statement: All authors declare that they have no conflicts of interest related to this work.
Corresponding author: Ling He, PhD, Professor, Department of Gastroenterology, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, No. 445 Bayi Avenue, Nanchang 330006, Jiangxi Province, China. heling118@126.com
Received: December 28, 2025 Revised: January 13, 2026 Accepted: January 23, 2026 Published online: August 27, 2026 Processing time: 235 Days and 2.5 Hours
Abstract
Hepatic fibrosis (HF) is a progressive condition driven by persistent activation of hepatic stellate cells (HSCs), metabolic dysregulation, and inflammatory signaling. Emerging evidence identifies the nuclear receptor NR1D1 as a central node linking circadian rhythms, HIF-1α signaling, and ammonia-mediated HSC activation, providing a mechanistic framework for chrono-metabolic therapeutic strategies. Preclinical studies demonstrate that pharmacological or natural compound-mediated modulation of NR1D1, including Hedyotis diffusa, ferulic acid, and dihydroartemisinin, restores circadian and metabolic homeostasis, attenuates HSC activation, and reduces extracellular matrix deposition. Integrative chrono-informed interventions leveraging NR1D1 offer potential advantages over conventional single-target therapies by synchronizing drug action with endogenous circadian oscillations, optimizing dosing, and enabling multi-pathway modulation. This review highlights the NR1D1-centered chrono-metabolic axis as a promising therapeutic target for HF, emphasizing translational potential and the need for preclinical and early-phase clinical validation.
Core Tip: This review summarizes the NR1D1-centered chrono-metabolic regulation of hepatic fibrosis, detailing how circadian rhythms, HIF-1α signaling, and ammonia-mediated hepatic stellate cell activation converge. It emphasizes the therapeutic potential of chrono-informed interventions using pharmacological agents and natural compounds, offering a translational roadmap for more precise and effective antifibrotic strategies.
