TGM2 drives microglial senescence by inhibiting autophagy via the PI3K/AKT/mTORC1 pathway.

Microglial senescence is increasingly recognized as a driver of age-related neurodegeneration by impairing autophagic clearance and exacerbating neuroinflammation. However, the molecular mechanisms coupling senescence to autophagy dysfunction remain unclear. Here we identify transglutaminase 2 (TGM2) as a critical regulator linking these processes. We show that TGM2 is selectively upregulated in senescent microglia, where it assembles a previously unrecognized signaling complex with 14-3-3γ (YWHAG) and PI3K (p85α). This complex sustains AKT phosphorylation, constitutively activates mTORC1, and thereby inhibits autophagic flux. Pharmacological inhibition of TGM2 with cystamine dihydrochloride (CD) reduces this complex, restores autophagy, attenuates senescence-associated secretory phenotype (SASP) and reactive oxygen species (ROS) levels, and significantly reverses cognitive and motor deficits in aged mice. These findings support a model in which TGM2-related signaling is linked to microglial autophagy dysfunction and senescence, suggesting that targeting TGM2 may offer a novel therapeutic approach for age-related neurodegenerative disorders.