Hepatocyte BDNF Acts as a Novel Immune Checkpoint to Restrain TLR4‐Mediated Acute Hepatitis

ABSTRACT Acute hepatitis is a major pathological process underlying acute liver injury (ALI) and acute liver failure (ALF), both of which are associated with high mortality. 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‐derived 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‐silencing transcription factor. Restoration of endogenous BDNF or exogenous administration of recombinant BDNF significantly alleviates LPS/DGal‐induced ALI/ALF. Correlation analysis and proteomic profiling reveal that BDNF exerts potent anti‐inflammatory effects by directly binding to and antagonizing Toll‐like receptor 4 (TLR4) on macrophages. Structural analysis identifies amino acids 233–244 of BDNF as the key functional domain responsible for this effect. A synthetic 12‐mer peptide derived from this region, termed BDP12, retains TLR4‐antagonizing ability, demonstrating strong anti‐inflammatory efficacy and a favorable safety profile in cultured macrophages and mouse ALI/ALF models. In conclusion, this study identifies hepatocyte‐derived 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‐mediated ALI/ALF.