FASN-dependent lipogenesis controls macrophage efferocytosis in alcohol-associated liver disease.

BACKGROUND & AIMS: Defective clearance of apoptotic hepatocytes contributes to inflammation and progression of alcohol-associated liver disease (ALD), but the mechanisms regulating macrophage efferocytosis during alcohol exposure remain unclear. We investigated whether fatty acid synthase (FASN)-dependent lipid metabolism controls hepatic macrophage efferocytosis in ALD. METHODS: Human liver tissues from patients with alcohol-related cirrhosis (AC) and controls (n = 18/group), together with experimental ALD mouse models (n = 6/group), were analyzed for hepatocyte apoptosis and hepatic macrophage alterations. Transcriptomic profiling (n = 3/group), pharmacological inhibition, and myeloid- or Kupffer cell-specific Fasn knockout mice (n = 6/group) were used to define the role and mechanism of FASN-mediated lipogenesis in macrophage efferocytosis. RESULTS: In patients with AC, hepatocyte apoptosis was markedly increased compared with controls (p < 0.0001), accompanied by increased accumulation of CD68-positive inflammatory macrophages (p < 0.001). In experimental ALD mice, hepatocyte apoptosis and monocyte-derived macrophage infiltration were also significantly increased (p < 0.0001). Mechanistically, ethanol impaired macrophage efferocytosis by more than 80% (p < 0.01). This was associated with inhibition of the PI3K/AKT/SREBP1 pathway, reduced FASN expression, and suppressed de novo lipogenesis. Reduced FASN expression decreased NRF2 activity and impaired TREM2 transcription, resulting in defective clearance of apoptotic cells. TREM2-positive hepatic macrophages were markedly reduced in both human AC and murine ALD (p < 0.0001). Consistently, Kupffer cell-specific Fasn deletion significantly aggravated hepatocyte apoptosis and liver injury in vivo (p < 0.01). CONCLUSIONS: Alcohol impairs macrophage efferocytosis by suppressing the PI3K/AKT/SREBP1-FASN-NRF2-TREM2 axis. Disruption of this lipogenic program promotes hepatocyte apoptosis and liver inflammation in ALD. IMPACT AND IMPLICATIONS: Alcohol-associated liver disease is characterized by hepatocyte death and ongoing inflammation, but the mechanisms that connect these processes to macrophage efferocytosis remain poorly understood. Our research revealed that ethanol suppresses FASN-dependent de novo lipogenesis and downstream NRF2-TREM2 signaling in hepatic macrophages. Impairment of lipogenesis compromises efferocytosis, leading to an accumulation of apoptotic hepatocytes and increased monocyte infiltration. These findings underscore the potential of targeting macrophage lipid metabolism as a therapeutic strategy in ALD. However, further translational validation is needed before clinical application.