Blocking Src kinase reduces neuroinflammation by activating microglial mitophagy in mice

In mice and cell models exposed to lipopolysaccharide, pharmacological inhibition of Src tyrosine kinase reduced neuroinflammatory responses. Proteomic analysis revealed that Src regulates microglial mitophagy through a pathway involving p62 UFMylation. Blocking Src kinase decreased the phosphorylation of the E3 ligase UFL1, which reduced the UFMylation of p62. Because UFMylation and ubiquitination compete for the same residue on p62, lower UFMylation facilitated p62 ubiquitination and subsequent degradation. This process induced microglial mitophagy and alleviated neuroinflammation. In the lipopolysaccharide-treated mice, Src inhibition ameliorated neuroinflammatory pathology and improved cognitive deficits via this p62-dependent mitophagy mechanism.