Redox Biol. 2026 Jun 6;95:104250. doi: 10.1016/j.redox.2026.104250. Online ahead of print.
ABSTRACT
Hyperhomocysteinemia (HHcy) is an independent risk factor for thrombotic cardiovascular events. We previously demonstrated that homocysteine (Hcy) amplifies platelet activation by promoting membrane remodeling and enhancing signaling through surface platforms such as integrin αIIbβ3 and G protein-coupled receptors. However, the mechanisms by which Hcy remodels platelet membrane lipid metabolism remain poorly understood. Here, using an integrated proteomic and lipidomic approach, we showed that Hcy disrupted platelet lipid homeostasis by impairing fatty acid β-oxidation (FAO), a metabolic pathway that depends on the coordinated action of peroxisomes and mitochondria. Proteomic profiling showed that Hcy downregulated peroxisome proliferator-activated receptor α (PPARα) and its downstream targets carnitine palmitoyltransferase 1 and 2 (CPT1/2), while lipidomic analysis confirmed the accumulation of medium and long-chain fatty acids, which promoted platelet reactive oxygen species production and mitochondrial dysfunction. Notably, pharmacological activation of PPARα with fenofibrate, a PPARα agonist, restored FAO in a CPT1/2-dependent manner, remodeled the platelet lipid membrane, and attenuated Hcy-potentiated platelet hyperactivation and thrombus formation. Collectively, these findings suggest a previously unrecognized Hcy-PPARα-FAO axis in platelet function and thrombosis, linking impaired peroxisomal and mitochondrial FAO to platelet hyperactivation, and support restoring membrane phospholipid dysregulation as a potential therapeutic strategy for HHcy-promoted thrombotic diseases.
PMID:42251786 | DOI:10.1016/j.redox.2026.104250