ALDOB K87 lactylation drives mitochondrial fission and metabolic reprogramming in pulmonary hypertension

Pulmonary hypertension (PH) is a life-threatening disorder characterized by progressive pulmonary vascular remodeling, occlusive arteriopathy, and right ventricular failure. However, the molecular mechanisms underlying these pathological hallmarks remain elusive. This study aimed to introduce aldolase B (ALDOB)-K87 lactylation as a critical regulator of mitochondrial fission and metabolic reprogramming in PH pathogenesis. Integrated lactylomic profiling in hypoxic human pulmonary artery smooth muscle cells (PASMCs) and validation in rodent PH models revealed that hypoxia-induced ALDOB-K87 lactylation amplified glycolytic flux, fostering lactate accumulation and self-reinforcing lactylation. Mechanistically, ALDOB lactylation recruited dynamin-related protein 1 (DRP1) to mitochondria via sentrin/SUMO-specific peptidase 3-mediated deSUMOylation of DRP1. This facilitated mitochondrial fragmentation, exacerbating PASMC proliferation, migration, and phenotypic switching. Sirtuin 1 serves as a delactylase for ALDOB, and its downregulation in PH sustains lactylation-driven pathology. Genetic or pharmacological suppression of ALDOB lactylation attenuates mitochondrial fission and PH progression in vivo, whereas lactylation-mimetic mutants exacerbate disease phenotypes. This study unveiled a lactate-ALDOB-DRP1 axis that bridged metabolic rewiring with mitochondrial dynamics, offering novel therapeutic targets for PH.