On July 28th, World Hepatitis Day raises global awareness of viral hepatitis and its broader impact on liver health. This occasion also highlights the need to address the complex pathophysiology underlying both acute and chronic liver diseases—a landscape where HMGB1 (High Mobility Group Box 1) has emerged as a key mediator of hepatic injury and fibrosis, and a promising therapeutic target.
Liver damage, whether triggered by acetaminophen overdose, ischemia-reperfusion injury, nonalcoholic fatty liver disease (NAFLD), or alcohol-associated liver disease (ALD), is increasingly linked to HMGB1-mediated inflammatory responses. Once released by necrotic hepatocytes, HMGB1 acts as a danger-associated molecular pattern (DAMP), amplifying inflammation through interaction with receptors such as RAGE and TLR4. These pathways activate pro-inflammatory cascades including NF-κB and MAPK, driving progression from injury to fibrosis and even hepatocellular carcinoma (HCC).
HMGB1 in acute liver injury
In models of acute liver injury (ALI), such as acetaminophen overdose, HMGB1 drives immune cell infiltration and cytokine production through the HMGB1–TLR4 pathway. Targeted inhibition of HMGB1—via monoclonal antibodies, HMGB1-release blockers, or receptor antagonists—has shown efficacy in reducing hepatic necrosis and systemic inflammation in preclinical models.
HMGB1 in chronic liver disease and fibrosis
In liver fibrosis, HMGB1 contributes to HSC activation, myofibroblast transdifferentiation, and extracellular matrix (ECM) remodeling. It also shapes the macrophage response—promoting M1 or M2 polarization depending on the hepatic microenvironment—further influencing fibrosis outcomes.
Moreover, in hepatocellular carcinoma (HCC), the HMGB1–RAGE interaction supports tumor cell proliferation, immune evasion, and angiogenesis, suggesting a role for HMGB1 not only in inflammation but also in oncogenesis.
HMGB1 stands at the intersection of inflammation, fibrosis, and tumorigenesis, offering both a mechanistic insight and a translational opportunity.
At HMGBiotech , we are dedicated to supporting cutting-edge research on HMGB1 and its role in liver diseases.
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