Autophagy-mediated Kupffer cell polarization in liver cirrhosis reversal: Mechanistic insights and therapeutic strategies.

Liver cirrhosis, an advanced end-stage liver disease characterized by extensive hepatic fibrosis, is a leading cause of mortality and morbidity worldwide. Despite its prevalence, there is no specific treatment to prevent fibrosis progression, with liver transplantation remaining the only definitive option for patients with advanced cirrhotic liver disease. The activation of hepatic stellate cells (HSCs) by proinflammatory M1-type Kupffer cells (KCs) is a key driver of fibrosis. Activated HSCs further exacerbate fibrosis by recruiting bone marrow-derived macrophages (BMDMs) through chemokine signaling, which induces alpha-smooth muscle actin (alpha-SMA) expression. Autophagy, a cellular process responsible for degrading damaged organelles and protein aggregates, is vital for maintaining liver physiology and metabolic balance. It also plays a significant role in the pathogenesis of fibrosis. Compounds that promote KC autophagy can polarize KCs toward an anti-inflammatory M2 phenotype, disrupting signaling pathways that activate HSCs and recruit BMDMs to injured liver tissue. This approach has been identified as a promising therapeutic strategy to combat liver fibrosis. This review highlights various strategies to activate KC autophagy and modulate KC polarization, offering insights into novel therapeutic targets for treating liver fibrosis and preventing cirrhosis progression.