E3 ubiquitin ligase TRIM38 regulates macrophage polarization to reduce hepatic inflammation by interacting with HSPA5

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses pathologies from simple steatosis and steatohepatitis (MASH) to cirrhosis. Hepatic inflammation is a common cause of liver pathogenesis, with macrophage activation as a key indicator of both acute and chronic liver dysfunction. While M1 macrophages promote inflammation and M2 macrophages suppress it, their roles in MASLD are dynamic and shift according to disease stage and liver microenvironment. Tripartite motif (TRIM) family proteins, which possess E3 ubiquitin ligase activity, are involved in various cellular processes, including intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy, and carcinogenesis. TRIM38 negatively regulates innate immunity and inflammation triggered by viruses, Toll-like receptor 3 and 4, and tumor necrosis factor α/interleukin-1β signaling; however, its role in liver pathogenesis remains unclear. This study investigates the role of macrophage TRIM38 in metabolic liver disease to identify key targets for controlling inflammation. TRIM38 overexpression suppressed lipopolysaccharide-induced macrophage activation and metabolic stress-induced hepatic lipid accumulation. Mechanistically, TRIM38 interacted with heat shock protein family A member 5 (HSPA5) and stabilized it via K63-dependent ubiquitination. This TRIM38-HSPA5 axis promoted the expression of M2 macrophage markers (arginase 1 and retinoic acid-related orphan receptor α), thereby ameliorating liver steatosis. Single-cell RNA sequencing revealed significant downregulation of TRIM38 expression in the liver macrophages of patients with MASLD and negative regulation of liver inflammation via modulation of macrophage polarization. Hence, macrophage TRIM38 suppresses metabolic liver disease progression via HSPA5-mediated M2 macrophage polarization and provides insights into potential therapeutic targets.