Metformin Stabilizes the Abdominal Aorta in Aneurysm by Restoring VSMC Mitochondrial Homeostasis via the AMPK-SIRT1-PGC-1α Axis

BACKGROUNDAbdominal aortic aneurysm (AAA) is a life-threatening condition with >80% mortality upon rupture and no effective pharmacotherapy available. Despite epidemiological evidence linking metformin use to reduced AAA progression, its mechanism remains elusive. Notably, peroxisome proliferator-activated receptor {gamma} coactivator 1 (PGC-1, encoded by Ppargc1a) is downregulated in human AAA, yet its functional role in metformins protection is unknown. METHODSWe employed porcine pancreatic elastase (PPE)-induced murine AAA, VSMC-specific Ppargc1a knockout (Ppargc1aVSMC-KO), primary VSMC senescence models, and pharmacological inhibition (Compound C for AMPK; Ex-527 for SIRT1) to define the AMPK-SIRT1-PGC-1 axis. RESULTSMetformin significantly inhibited AAA expansion, suppressed VSMC senescence (p53/p21{downarrow}, SA-{beta}-gal{downarrow}), and preserved contractile phenotype (SMTN{uparrow}, IL-6/TNF-{downarrow}). Crucially, all benefits were abrogated in Ppargc1aVSMC-KO mice, which exhibited accelerated aneurysm growth, mitochondrial fragmentation, ATP depletion, and ROS accumulation. Mechanistically, metformin activated AMPK/SIRT1 to upregulate PGC-1; AMPK or SIRT1 inhibition blocked this cascade and reversed protection. CONCLUSIONMetformin restrains AAA by restoring VSMC mitochondrial homeostasis via the AMPK/SIRT1[->]PGC-1 axis, positioning PGC-1 as a non-redundant, cell-autonomous guardian against vascular degeneration. These findings provide a mechanistic foundation for repurposing metformin and developing PGC-1-targeted therapies in AAA.