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Yet, no effective treatment is currently available, underscoring the pressing need for novel therapeutic targets. By integrating multiple transcriptomic datasets, this study finds that the expression of brain\u2010derived neurotrophic factor (BDNF) is consistently downregulated in hepatocytes across various ALI\/ALF models. Mechanistically, this downregulation is attributed to transcriptional repression of BDNF by RE1\u2010silencing transcription factor. Restoration of endogenous BDNF or exogenous administration of recombinant BDNF significantly alleviates LPS\/DGal\u2010induced ALI\/ALF. Correlation analysis and proteomic profiling reveal that BDNF exerts potent anti\u2010inflammatory effects by directly binding to and antagonizing Toll\u2010like receptor 4 (TLR4) on macrophages. Structural analysis identifies amino acids 233\u2013244 of BDNF as the key functional domain responsible for this effect. A synthetic 12\u2010mer peptide derived from this region, termed BDP12, retains TLR4\u2010antagonizing ability, demonstrating strong anti\u2010inflammatory efficacy and a favorable safety profile in cultured macrophages and mouse ALI\/ALF models. In conclusion, this study identifies hepatocyte\u2010derived BDNF as an endogenous antagonist of TLR4 and a critical immune checkpoint in acute hepatitis. BDNF and its mimetic peptide BDP12 represent promising therapeutic candidates for treating acute hepatitis\u2010mediated ALI\/ALF.<\/jats:p>","DOI":"10.1002\/advs.202521164","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T20:05:34Z","timestamp":1774469134000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Hepatocyte BDNF Acts as a Novel Immune Checkpoint to Restrain TLR4\u2010Mediated Acute Hepatitis"],"prefix":"10.1002","volume":"13","author":[{"given":"Weiwei","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Cardiology and Medical Research Center the First Affiliated Hospital of Wenzhou Medical University  Wenzhou Zhejiang China"},{"name":"Affiliated Cangnan Hospital and Chemical Biology Research Center Wenzhou Medical University  Wenzhou Zhejiang 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