Revisiting cannabinoid receptor-2: a key regulator of hepatic steatosis, inflammatory cascades, and fibrotic progression.

Liver diseases constitute a major global health challenge, affecting over 25% of the world's population, with metabolic dysfunction-associated steatotic liver disease (MASLD) emerging as the most prevalent chronic liver disorder and a leading cause of cirrhosis, hepatocellular carcinoma, and liver-related mortality. Despite its increasing burden, effective and targeted pharmacological therapies remain limited, highlighting a critical need to identify novel molecular targets and mechanistic pathways for therapeutic intervention. The endocannabinoid system, comprising cannabinoid receptors, endogenous ligands, and the enzymes involved in their synthesis and degradation, has gained significant attention as a regulator of hepatic physiology and disease. Although cannabinoid receptor 1 (CB1) has been extensively characterized, cannabinoid receptor 2 (CB2), previously considered predominantly immunomodulatory, is now recognized as a key regulator of hepatic lipid metabolism, inflammatory signaling, and fibrogenesis. Metabolic dysfunction induces hepatic lipid accumulation, oxidative stress, and endoplasmic reticulum stress, triggering inflammatory cascades that drive disease progression from simple steatosis to MASLD, metabolic dysfunction-associated steatohepatitis (MASH), and ultimately fibrosis. Emerging evidence indicates that CB2 activation exerts anti-steatotic, anti-inflammatory, and anti-fibrotic effects through cell-specific mechanisms in hepatocytes, Kupffer cells, and hepatic stellate cells. This review revisits CB2 as a central regulator of hepatic pathophysiology, integrating mechanistic insights with preclinical and clinical evidence. Collectively, targeting CB2 signaling presents a promising therapeutic strategy to mitigate steatosis, inflammatory cascades, and fibrotic progression in chronic liver diseases.