Metformin hijacks AMPK-ERK1/2 signaling to trigger a pathogenic "selection trap" and thymic atrophy.

Metformin shows clinical promise beyond diabetes, yet its immunological safety in non-diabetic contexts remains uncertain. We found that metformin induces apoptosis in double-positive thymocytes across various mouse models and, importantly, creates a "selection trap" by promoting phenotypic maturation (TCRβCD69) while simultaneously triggering their elimination. Mechanistically, this trap is sprung via mitochondrial dysfunction initiated by complex I inhibition, which causes ATP depletion and elevated mitochondrial reactive oxygen species. This metabolic stress drives sustained AMP-activated protein kinase (AMPK) activation, repurposing extracellular signal-regulated kinase 1/2 signaling to expose the BH3 domain of B cell lymphoma-2 (Bcl-2), thereby neutralizing its anti-apoptotic function. Transcriptomics further reveal that AMPK remodels metabolic pathways to augment oxidative injury and energy crisis, facilitating apoptosis. Notably, thymotoxicity persists even at subtherapeutic doses (25 mg/kg), challenging metformin's indiscriminate use in non-diabetic populations due to risks to central immune homeostasis.