HMGB1 Exacerbates Intestinal Barrier Damage by Inducing Ferroptosis Through the TLR4/NF-κB/GPX4 Pathway in Ulcerative Colitis.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:40689397", "kind": "science-record", "revision": 4, "content_hash": "sha256:a117b3c0e689ef9cb4890138efcb0805798450437ee86d53a85d8f2b6a86a304", "created_at": "2026-11-01T20:30:47Z", "updated_at": "2026-11-01T22:56:52Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "HMGB1 Exacerbates Intestinal Barrier Damage by Inducing Ferroptosis Through the TLR4/NF-κB/GPX4 Pathway in Ulcerative Colitis.", "doi": "10.1155/mi/2395557", "pmid": "40689397", "authors": ["Nannan Zhu", "Xiaoyuan Ge", "Lixue Zhang", "Xinwen Chen", "Weizhen Xiang", "Qiao Mei"], "journal": "Mediators of inflammation", "year": 2025, "abstract": "Background: Intestinal barrier dysfunction and persistent inflammatory response are key pathophysiologic features of ulcerative colitis (UC). High mobility group box-1 protein (HMGB1), an important inflammatory mediator and immunomodulatory factor, has been shown to be involved in the pathogenesis of UC. However, the association between HMGB1 and intestinal barrier dysfunction is unclear. Methods: In this study, we investigated the mechanism of HMGB1 driving intestinal barrier damage by integrating clinical data, animal models, and cellular experiments in UC. First, HMGB1 levels and its correlation with intestinal barrier protein expression in UC patients were verified based on Gene Expression Omnibus (GEO) dataset GSE75214 analysis and western blotting (WB) assay. Subsequently, colitis was induced in C57BL/6J mice using dextran sodium sulfate (DSS) and intervened with dipotassium glycyrrhizinate (DPG), and the effects of HMGB1 on colonic inflammation, ferroptosis, and intestinal barrier were assessed by histopathological scoring, qRT-PCR, enzyme-linked immunosorbent assay (ELISA), WB assay, immunofluorescence, and transmission electron microscopy (TEM) examination. Lastly, the influence of HMGB1 on ferroptosis-related genes expression, TLR4/NF-κB/GPX4 pathway activation and intestinal barrier damage were revealed by transepithelial electrical resistance (TEER) value measures, FITC-dextran permeability detections, qRT-PCR, and WB assays in vitro Caco-2 cell models. Results: HMGB1 expression was significantly elevated in colonic tissues of UC patients (especially in active stage), and was negatively correlated with barrier protein expression. In DSS-induced colitis mouse model, HMGB1 upregulation accompanied by changes in TLR4, NF-κB, and GPX4 expression and ferroptosis-related genes upregulation, while inhibition of HMGB1 attenuated inflammation, restored barrier function, and reversed ferroptosis. Moreover, cellular experiments further confirmed HMGB1 induced ferroptosis and intestinal barrier damage in Caco-2 cells via the TLR4/NF-κB/GPX4 pathway. Conclusion: Our results suggest that HMGB1 drives ferroptosis through the TLR4/NF-κB/GPX4 signaling pathway, thereby exacerbating intestinal inflammation and barrier damage in UC. Targeting this pathway may provide a novel therapeutic strategy for UC.", "claims": [{"id": "claim-method", "statement": "Comparison between two groups were made by t-test, while one-way ANOVA was used for comparisons between three groups, and post hoc comparisons by LSD test.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40689397", "locator": "sections[16] \"2.14. 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