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However, the scientific basis for its efficacy and mechanisms remains unclear. Methods: The chemical composition of XXLP was analyzed via UPLC-ESI-MS\/MS. A colitis mouse model was established using DSS, and the therapeutic effects were assessed based on body weight, disease activity index (DAI), colon length, and histopathology. Inflammatory cytokines were measured using ELISA. Proteomic analysis and molecular docking identified key targets, which were validated using LPS-induced HT-29 cells via Western blot (WB), qRT-PCR, immunofluorescence (IF), and transmission electron microscopy (TEM). Gut microbiota composition was analyzed using 16S rRNA gene sequencing. Results: Analysis of XXLP led to the detection of 373 compounds. XXLP significantly improved colitis symptoms, including weight loss and colon shortening, and reduced the concentrations of inflammatory markers IL-1\u03b2, IL-18, TNF-\u03b1, and IL-6. Proteomics and molecular docking identified NADPH oxidase 2 (NOX2) as a key target of XXLP intervention in mice with colitis. qRT-PCR, WB, IF, and TEM results further confirmed that XXLP effectively suppressed the expression of NOX2 and its associated protein levels. Sequencing analysis of 16S rRNA showed that XXLP significantly increased the relative abundance of beneficial bacterial genera (Muribaculaceae and Ruminococcaceae) while markedly reducing the levels of harmful bacteria (Enterobacteriaceae). Correlation analysis revealed that specific microorganisms were correlated with NOX2-related protein expression and severity of colonic inflammation. Conclusions: XXLP effectively alleviates colitis by suppressing inflammatory responses. Its mechanism involves regulating the NOX2\/ROS\/mitochondria\/NLRP3 axis and altering gut microbiota composition, providing novel insights for colitis treatment.<\/jats:p>","DOI":"10.3390\/ph19030452","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T09:00:37Z","timestamp":1773219637000},"page":"452","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Xu Chunfu\u2019s Modified Xianglian Pill Regulates the NOX2\/ROS\/Mitochondria\/NLRP3 Axis to Treat Ulcerative Colitis"],"prefix":"10.3390","volume":"19","author":[{"given":"Shangling","family":"Mao","sequence":"first","affiliation":[{"name":"College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingru","family":"Bu","sequence":"additional","affiliation":[{"name":"College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2476-9397","authenticated-orcid":false,"given":"Wenfan","family":"Wei","sequence":"additional","affiliation":[{"name":"College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1581-1538","authenticated-orcid":false,"given":"Daqiang","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongfeng","family":"Hu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Xin\u2019an Medicine (Anhui University of Chinese Medicine), Ministry of Education, Hefei 230038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changzhong","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianming","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2188-6077","authenticated-orcid":false,"given":"Yue","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103655","DOI":"10.1016\/j.autrev.2024.103655","article-title":"Analysis of global prevalence, DALY and trends of inflammatory bowel disease and their correlations with sociodemographic index: Data from 1990 to 2019","volume":"23","author":"Dou","year":"2024","journal-title":"Autoimmun. 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