Pan HY, Chen WW, Liang JX, Sheng YY, Zhang WJ, Zhu XW, Wang SY, Yang GH, Liu Y, Xu TC. Pancreatic-liver crosstalk, novel molecular mediators, and 2025 therapeutic breakthroughs. World J Methodol 2026; 16(3): 118728 [DOI: 10.5662/wjm.v16.i3.118728]
Corresponding Author of This Article
Tian-Cheng Xu, MD, PhD, Academic Fellow, Consultant, Full Professor, Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, No. 138 Xianlin Avenue, Qixia District, Nanjing 210023, Jiangsu Province, China. xtc@njucm.edu.cn
Research Domain of This Article
Endocrinology & Metabolism
Article-Type of This Article
review-article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Hao-Yao Pan, Wei-Wei Chen, Jia-Xin Liang, Yi-Yang Sheng, Wen-Jing Zhang, Xue-Wen Zhu, Shuai-Yan Wang, Yun Liu, Tian-Cheng Xu, Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
Guan-Hu Yang, Department of Specialty Medicine, Ohio University, Athens, OH 45701, United States
Co-first authors: Hao-Yao Pan and Wei-Wei Chen.
Co-corresponding authors: Yun Liu and Tian-Cheng Xu.
Author contributions: Pan HY and Chen WW conceptualized and designed this review; Pan HY, Chen WW, Liang JX, Sheng YY, Zhang WJ and Zhu XW wrote the first draft of the manuscript; Wang SY was responsible for language polishing and linguistic refinement of the manuscript. Yang GH provided overall guidance on the research direction and academic framework of the review. All authors have reviewed and approved the final version of the manuscript. Pan HY was responsible for the core conceptualization and overall framework, while Chen WW was responsible for the creation of figures in the initial draft. Both authors contributed significantly to the writing of the core content of the manuscript and coordinated the writing process, making essential and irreplaceable contributions to the completion of the project, and thus qualified as the co-first authors of the paper. Liu Y and Xu TC served as the co-corresponding authors, playing key roles in quality control, academic depth enhancement, and final manuscript coordination. Liu Y applied for and secured funding for the research project, playing a crucial role in the overall design and quality control, ensuring the academic value and publication quality of the review. Xu TC focused on the academic depth and content rigor of the review, assuming key responsibilities for academic oversight, coordinating feedback from all authors on revised versions, leading responses to reviewer comments during the submission process, and guiding further improvements to the manuscript, ensuring the academic quality and publication standards of the review.
Supported by National Natural Science Foundation of China Youth Science Fund Project, No. 82305376; Young Talent Support Program of the China Association for Acupuncture-Moxibustion, No. 2024-2026ZGZJXH-QNRC005; 2024 Jiangsu Provincial Young Scientific and Technological Talent Support Program, No. JSTJ-2024-380; and Talent Cultivation Program for Young Researchers (Category A), Key Laboratory of the Ministry of Education Project, No. Zyqt202501 and No. Zyqt202503.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Corresponding author: Tian-Cheng Xu, MD, PhD, Academic Fellow, Consultant, Full Professor, Key Laboratory of Acupuncture and Medicine Research of Ministry of Education, Nanjing University of Chinese Medicine, No. 138 Xianlin Avenue, Qixia District, Nanjing 210023, Jiangsu Province, China. xtc@njucm.edu.cn
Received: January 12, 2026 Revised: January 31, 2026 Accepted: March 4, 2026 Published online: September 20, 2026 Processing time: 182 Days and 4 Hours
Abstract
Obesity, a global public health crisis driven by dysregulated systemic energy homeostasis, is increasingly recognized as a disorder of interorgan communication, with the pancreas and liver serving as central interconnected metabolic hubs. Their bidirectional crosstalk, mediated through neural and humoral pathways, is a key driver of disease progression. Recent breakthroughs have uncovered novel molecular mechanisms amplifying this pathogenic axis: Adipocyte-derived exosomes carrying miR-138-5p directly target pancreatic β-cell SOX4, suppressing insulin secretion and promoting apoptosis, while hepatic RNA demethylase ALKBH5 stabilizes glucagon receptor mRNA and activates lipogenic pathways, exacerbating hyperglycemia and steatosis. Further, colonic inflammation activates hepatic ERK signaling, which is converted into neural signals by the liver and precisely delivered to the pancreas through the liver-pancreas vagus nerve circuit, driving adaptive β-cell proliferation in early obesity by releasing neurotransmitters such as acetylcholine. Traditional pathogenic loops persist: Pancreatic exocrine insufficiency disrupts gut-liver homeostasis, inducing systemic inflammation, and hepatic free fatty acid flux exerts direct and immune-mediated lipotoxicity on pancreatic β-cells, forming a self-perpetuating vicious cycle. Emerging interventions target this axis: GLP-1/GIP dual agonists (e.g., tirzepatide) demonstrate remarkable efficacy in weight loss and non-alcoholic steatohepatitis remission, while time-restricted feeding (e.g., 16:8 regimen) reduces liver fat through circadian and metabolic pathway activation, independent of caloric restriction. This review synthesizes novel interorgan signaling mechanisms and 2025 therapeutic breakthroughs, emphasizing the pancreas-liver axis as a critical target for obesity management.
Core Tip: This minireview synthesizes the key role of the pancreas-liver axis in the pathogenesis of obesity, highlighting novel molecular mediators (e.g. adipocyte-derived exosomal miR-138-5p and hepatic ALKBH5) and neuroimmune pathways that drive pancreatic-liver crosstalk. It further discusses emerging therapeutic breakthroughs, including GLP-1/GIP dual agonists and intermittent fasting, which aim to improve metabolic outcomes and provide comprehensive strategies for obesity management and prevention of related metabolic diseases.
