Src inhibition attenuates neuroinflammation via promoting p62 UFMylation-dependent microglial mitophagy

Src tyrosine kinase, a prototypical oncogene, has recently emerged as a critical modulator of neuroinflammation. However, the precise molecular mechanisms underlying its regulatory role remain poorly characterized. Herein, pharmacological inhibition of Src attenuated lipopolysaccharide-induced neuroinflammatory responses in both in vivo and in vitro experiments. Proteomic analysis identified that microglial mitophagy and p62 UFMylation were involved in Src-mediated neuroinflammation. Further studies demonstrated that Src inhibition reduced the phosphorylation of UFL1, the E3 ligase of UFM1 conjugation, which correlated with decreased UFMylation of p62. Notably, the function of p62 was regulated by a dynamic interplay between UFMylation and ubiquitination. Consequently, diminished p62 UFMylation competitively facilitated ubiquitination of p62 at the same residue. This led to p62 degradation and induced microglial mitophagy, ultimately alleviating neuroinflammation. Moreover, Src inhibition significantly ameliorated neuroinflammatory pathology and cognitive deficits in LPS-challenged mice, an effect attributed to p62 UFMylation-mediated microglial mitophagy. Collectively, our findings revealed that the Src-UFL1-p62 signaling axis governing microglial mitophagy and neuroimmune homeostasis, positioning Src kinase as a promising therapeutic target for Alzheimer's disease and related neuroinflammatory disorders.