Rhapontin activating nuclear factor erythroid 2-related factor 2 to ameliorate Parkinson’s disease-associated gastrointestinal dysfunction

This commentary provides a critical evaluation of the study by Wang <i>et al</i>, 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 <i>via</i> 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 (<i>KEAP1</i> and p62). In addition, it is necessary to improve refined behavioral tests, focusing on incorporating cognitive function and anxiety-related assessment items.