PPARα deficiency exacerbates atherosclerosis progressing through enhancing pTh17 cells-macrophage crosstalk.

Atherosclerosis (AS) is a chronic inflammatory disease driven by hypercholesterolemia and characterized by the accumulation of lipid-rich plaques within arterial walls. Although the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) is known to regulate lipid metabolism and inflammation, the precise immunological mechanisms underlying its anti-atherosclerotic effects remain elusive. Here, we investigated the role of PPARα in atherosclerosis using both human and murine models, focusing on its regulation of pathogenic Th17 (pTh17) cell differentiation. Clinical data revealed that PPARα expression in CD4+ T cells significantly decreased with the progression of atherosclerosis. Functionally, PPARα deficiency accelerated plaque formation and instability by selectively promoting pTh17 differentiation, which subsequently impaired macrophage efferocytosis via paracrine crosstalk. Mechanistically, PPARα loss disrupted mitochondrial homeostasis, triggering mitochondrial DNA (mtDNA) leakage and activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-ERK cascade to intrinsically drive pTh17 commitment. Critically, either genetic ablation of STING or pharmacological activation of PPARα reversed these detrimental effects, suppressing pTh17 expansion and restoring macrophage efferocytosis. These findings establish PPARα as a vital metabolic-immune checkpoint, providing a mechanistic rationale for targeting the PPARα-cGAS-STING axis to concurrently attenuate pathogenic T cell inflammation and stabilize atherosclerotic plaques.