Microbial Peptidoglycan Activates Mitophagy via Binding Autophagy Adaptor p62 to Protect Liver Health

Since the gut microbiota significantly influences liver health, identifying specific bacterial factors capable of directly modulating hepatocyte mitophagy may offer new therapeutic avenues. Here, we identify bacterial peptidoglycan (PGN), a ubiquitous cell wall component, as a potent inducer of hepatocyte mitophagy and a protective agent against liver fibrosis.

We demonstrate that PGN alleviates drug-induced hepatocyte death in vitro and attenuates carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice. Mechanistically, PGN is internalized by hepatocytes, localizes to mitochondria, and initiates mitophagy by binding directly to the autophagic adaptor p62 (also known as SQSTM1). The essential role of this pathway was confirmed, as genetic ablation of p62 in hepatocytes completely abolished PGN-induced mitophagy.