AIBP deficiency drives MAFLD advancement via ITGβ3 mediated lipid metabolism disruption and pro-inflammatory activation.

Metabolic-associated fatty liver disease (MAFLD), the most prevalent chronic hepatic disorder globally, is pathologically characterized by excessive intrahepatic lipid deposition, oxidative stress, and chronic low-grade inflammation. Apolipoprotein A-I binding protein (AIBP), a critical modulator of lipid metabolism, cellular signaling pathways, inflammatory responses, and metabolic homeostasis, has not been thoroughly investigated in the context of MAFLD pathogenesis. In this study, we identified a significant downregulation of AIBP expression in both high-fat diet (HFD)-induced MAFLD murine models and palmitic acid (PA)-treated HepG2 cells. Systemic AIBP deficiency exacerbated metabolic dysregulation and induced profound perturbations in hepatic architecture and function, culminating in aggravated liver injury. This was evidenced by enhanced steatosis, elevated pro-inflammatory cytokine production, and increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Transcriptomic profiling and molecular characterization of AIBP-deficient HepG2 cells corroborated these pathological alterations. Mechanistic investigations revealed that AIBP silencing potentiates hepatic damage through integrin β3 (ITGβ3)-mediated hyperactivation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling cascade. Notably, hepatocyte-specific AIBP overexpression effectively ameliorated these metabolic and inflammatory aberrations. Collectively, our findings establish AIBP as a pivotal hepatoprotective regulator in MAFLD pathogenesis and propose a novel therapeutic paradigm for MAFLD and associated metabolic disorders through targeted AIBP modulation. This study provides compelling evidence for the development of AIBP-centered therapeutic strategies to mitigate MAFLD progression.