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World J Gastroenterol. Mar 14, 2026; 32(10): 115334
Published online Mar 14, 2026. doi: 10.3748/wjg.v32.i10.115334
Published online Mar 14, 2026. doi: 10.3748/wjg.v32.i10.115334
Integrative study reveals NR1D1 mediates Hedyotis diffusa’s antifibrosis via hypoxia inducible factor-1/ammonia axis
Si-Wei Xia, Huan Liu, Kai-Yao Yang, Yi-Jie Gao, Meng-Ru Zhang, Jing-Wen Zhou, Feng Zhang, Li Chen, Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
De-Song Kong, Nanjing Hospital of Chinese Medicine, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing 210022, Jiangsu Province, China
Hong-Yan Wu, Department of Pharmacy, Yancheng Vocational Institute of Health Sciences, Yancheng Vocational Institute of Health Sciences, Yancheng 224005, Jiangsu Province, China
Co-first authors: Si-Wei Xia and Huan Liu.
Co-corresponding authors: Feng Zhang and Li Chen.
Author contributions: Xia SW and Liu H contributed to conceptualization, investigation, validation, data curation, writing original draft; Yang KY and Gao YJ contributed to validation, data curation; Zhang MR, Zhou JW, and Kong DS contributed to software, visualization, formal analysis; Wu HY, Zhang F and Chen L contributed to methodology, project administration, conceptualization, funding acquisition, supervision, writing review and editing.
Supported by the Jiangsu Province Traditional Chinese Medicine Science and Technology Development Plan Project, No. QN202304, No. ZD202402 and No. QN202112; the National Natural Science Foundation of China, No. 82173874 and No. 82274339; Noncommunicable Chronic Diseases-National Science and Technology Major Project, No. 2024ZD0530800; the Jiangsu Higher Education Institution Innovative Research Team for Science and Technology (2023), No. 56; the Jiangsu Province Engineering Research Center for Cardiovascular and Cerebrovascular Disease and Cancer Prevention and Control (2022), No. 85; the Postgraduate Research and Practice Innovation Program of Jiangsu Province, No. KYCX242311; and Natural Science Foundation for Colleges and Universities in Jiangsu Province, No. 23KJB360005.
Institutional review board statement: This study does not involve any human experiments.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Jiangsu Vocational College of Medicine (IACUC protocol No. SYLL-2023-004).
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The data supporting the findings of this study are available from the corresponding author upon reasonable request.
Corresponding author: Li Chen, PhD, Lecturer, Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, No. 138 Xianlin Avenue, Nanjing 210023, Jiangsu Province, China.
Received: October 17, 2025
Revised: November 10, 2025
Accepted: December 16, 2025
Published online: March 14, 2026
Processing time: 138 Days and 22.1 Hours
Revised: November 10, 2025
Accepted: December 16, 2025
Published online: March 14, 2026
Processing time: 138 Days and 22.1 Hours
Core Tip
Core Tip: This study reveals a novel antifibrotic mechanism of Hedyotis diffusa, demonstrating that its bioactive components alleviate hepatic fibrosis by restoring expression of the circadian rhythm gene NR1D1 expression. NR1D1 acts as an upstream regulator, inhibiting hypoxia inducible factor-1 signaling and restoring urea cycle function, thereby reducing hepatic ammonia accumulation and interrupting the vicious cycle of ammonia-induced hepatic stellate cell activation. These findings position circadian rhythm-metabolism interplay as a promising therapeutic axis for liver fibrosis treatment.