Excessive fatty acid oxidation drives lipotoxic vascular aging: therapeutic targeting of the PPAR-α/CPT1A Axis by betulinic acid

Background Metabolic overload accelerates vascular aging, yet the mechanistic contribution of fatty acid oxidation (FAO) to lipotoxic vascular senescence remains unclear. PPAR-α is a master regulator of FAO through CPT1A activation. We hypothesized that pathological overactivation of the PPAR-α/CPT1A axis drives vascular senescence and that pharmacological suppression restores vascular homeostasis. Methods Lipotoxic senescence was induced in mouse aortic smooth muscle cells (MASMCs) using oleic acid (OA). Transcriptomic profiling identified pathways reversed by betulinic acid (BA). Direct interaction between BA and PPAR-α was assessed, and mechanistic dependency was tested using PPAR-α overexpression. In vivo efficacy was evaluated in ApoE-/- mice fed a high-fat diet. Results Transcriptomic enrichment identified PPAR-α signaling and fatty acid metabolism as dominant nodes reversed by BA. BA directly bound PPAR-α (KD = 4.07 μM), suppressed CPT1A expression, reduced mitochondrial hyper-respiration and ROS accumulation, and decreased senescence markers (P16, P21, P53; all P < 0.05). Importantly, PPAR-α overexpression restored FAO activity and abolished the anti-senescent effects of BA, confirming pathway dependency. In ApoE-/- mice, BA significantly reduced arterial stiffness and carotid intima-media thickness, accompanied by decreased vascular lipid deposition and senescence burden. Conclusions Our findings identify excessive FAO as a previously underappreciated driver of lipotoxic vascular aging. Targeting the PPAR-α/CPT1A axis restores metabolic balance and ameliorates vascular senescence, highlighting FAO modulation as a potential therapeutic strategy in metabolic vascular disease.