Key result
Macrophage ALDH2 lactylation links to vulnerable coronary plaques, while mannose reduces atherosclerosis in mice.
Why the study?
The adipose-vascular cross-organ mechanisms by which metabolic syndrome accelerates atherosclerosis remain unclear, and whether elevated ALDH2 lactylation in adipose tissue macrophages drives metabolic reprogramming and atherosclerotic progression or can be therapeutically targeted is undetermined.
Does targeting ALDH2 lactylation via SIRT3 activation (honokiol) or mannose supplementation reduce atherosclerotic lesion burden and improve ATM metabolic reprogramming in obese-atherosclerosis mice?
Cohort (n=40)
Does targeting ALDH2 lactylation via SIRT3 activation (honokiol) or mannose supplementation reduce atherosclerotic lesion burden and improve ATM metabolic reprogramming in obese-atherosclerosis mice?
ALDH2 lactylation in adipose tissue macrophages links adipose dysfunction to vascular inflammation and plaque vulnerability, representing a potential therapeutic target for metabolic syndrome-associated atherosclerosis.
Answers are grounded in this paper and cite their sources.
Should not change clinical practice in metabolic syndrome; hypothesis-generating for ALDH2 lactylation as a therapeutic target.
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.
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Lou et al. (2026) conducted a cohort in Metabolic syndrome-associated atherosclerosis (n=40). ALDH2 lactylation in adipose tissue macrophages was evaluated on Correlation of ALDH2 lactylation with abdominal adiposity and vulnerable coronary plaques. ALDH2 lactylation in adipose tissue macrophages correlated with vulnerable plaques in a 40-patient MetS cohort, while mannose supplementation reduced atherosclerotic burden in obese-AS mice.
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