Chen YX, Sun NQ, Mo SJ. Rhapontin activating nuclear factor erythroid 2-related factor 2 to ameliorate Parkinson’s disease-associated gastrointestinal dysfunction. World J Gastroenterol 2026; 32(4): 114468 [DOI: 10.3748/wjg.v32.i4.114468]
Corresponding Author of This Article
Sai-Jun Mo, PhD, Associate Professor, Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, No. 100 Science Avenue, Zhongyuan District, Zhengzhou 450001, Henan Province, China. sjmo@zzu.edu.cn
Research Domain of This Article
Oncology
Article-Type of This Article
Letter to the Editor
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/
Yi-Xiao Chen, Sai-Jun Mo, Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
Na-Qi Sun, Department of Pathophysiology, School of Basic Medical Sciences, The Third Clinical School of Zhengzhou University, Zhengzhou 450000, Henan Province, China
Co-first authors: Yi-Xiao Chen and Na-Qi Sun.
Author contributions: Mo SJ provided the research idea and participated in the revision of the manuscript; Chen YX composed the manuscript and participated in the revision of the manuscript; Sun NQ participated in the revision of the manuscript.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Sai-Jun Mo, PhD, Associate Professor, Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, No. 100 Science Avenue, Zhongyuan District, Zhengzhou 450001, Henan Province, China. sjmo@zzu.edu.cn
Received: September 22, 2025 Revised: November 16, 2025 Accepted: December 26, 2025 Published online: January 28, 2026 Processing time: 124 Days and 18.5 Hours
Abstract
This commentary provides a critical evaluation of the study by Wang et al, which focuses on rhapontin activating colonic nuclear factor erythroid 2-related factor 2 (NRF2) to explore its therapeutic potential for Parkinson’s disease (PD)-associated gastrointestinal dysfunction. The commentary acknowledges the academic value of the study: It has not only validated intestinal NRF2 as a therapeutic target for PD but also provided experimental support for the “enteric pathology hypothesis”. However, several key gaps remain unresolved in the study. At the gut microbiota level, the exploration of the causal relationship of the microbiota is insufficient, with no validation conducted via methods such as fecal microbiota transplantation; additionally, it fails to systematically integrate the gut-brain axis with PD and does not assess the impact of rhapontin on the composition or function of the gut microbiota. At the pathway mechanism level, it lacks an analysis of the crosstalk between NRF2 and other rhapontin-targeted pathways, including nuclear factor kappa-B, mitogen-activated protein kinase, adenosine monophosphate-activated protein kinase, and sirtuin 1. At the experimental method level, the behavioral testing methods for PD mouse models and the limitations of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse models need attention. Additionally, certain flaws exist in some experimental result figures. Furthermore, this commentary puts forward improvement suggestions for the study. Future research should prioritize multi-omics analysis, encompassing combined metabolomics and metagenomics detection, while conducting mechanistic validation of NRF2-interacting molecules (KEAP1 and p62). In addition, it is necessary to improve refined behavioral tests, focusing on incorporating cognitive function and anxiety-related assessment items.
Core Tip: This commentary argues that realizing rhapontin’s potential in ameliorating Parkinson’s disease (PD)-associated gastrointestinal dysfunction requires a systems-level understanding of its interaction with the gut microbiota and signaling networks beyond nuclear factor erythroid 2-related factor 2 (NRF2) (e.g., nuclear factor kappa-B, adenosine monophosphate-activated protein kinase, sirtuin 1). It emphasizes that rhapontin’s colonic NRF2-mediated local anti-inflammatory effects support PD’s “enteric pathology hypothesis” and highlight colonic NRF2 as a priority intervention target.
