ALDH2 lactylation in adipose tissue macrophages: a putative metabolic-immune switch in metabolic syndrome-associated atherosclerosis
B Lou, C Wang, X Y Zhang, Z Y Zhang, Z Y Yuan, J Q SheAbstract
Background
Metabolic syndrome (MetS) accelerates atherosclerosis (AS) via adipose inflammation, but the "adipose-vascular" cross-organ mechanisms remain unclear. Our preliminary data show elevated aldehyde dehydrogenase 2 (ALDH2) lactylation in adipose tissue macrophages (ATMs) from MetS-AS patients and obese-AS mice, suggesting a pathogenic role in MetS-related atherogenesis.
Objective
To determine whether ALDH2 lactylation drives ATM metabolic reprogramming and atherosclerotic progression, and to evaluate the translational potential of targeting this modification via SIRT3-mediated delactylation or mannose-based intervention.
Methods
We analyzed ALDH2 lactylation-coronary plaque correlation in a prospective MetS cohort (n=40) by coronary CTA. Macrophage-specific Aldh2 knock-in and AAV-PCSK9 obese-AS mice were generated; scRNA-seq, IP-MS, and Seahorse assays explored mechanisms. Therapeutic rescue experiments were performed using SIRT3 activation (honokiol) and mannose treatment.
Results
MetS patients displayed markedly increased ALDH2 lactylation in ATMs, correlating with abdominal adiposity and vulnerable plaques (Fig1). In obese-AS mice, hyper-lactylation of ALDH2 promoted a glycolytic switch and pro-inflammatory polarization in ATMs(Fig2). Mannose supplementation restored mitochondrial oxidative metabolism and reduced atherosclerotic lesion burden.
Conclusion
ALDH2 lactylation links adipose dysfunction to vascular inflammation, offering a novel precision therapeutic target for MetS-associated cardiovascular disease.