Targeting ALDOA Lactylation Reverses Vascular Remodeling in Pulmonary Hypertension by Disrupting Actin Polymerization and YAP Activation.

AARS1-mediated ALDOA K42 lactylation is elevated in hypoxic pulmonary arterial smooth muscle cells and human PH tissues, and its disruption attenuates vascular remodeling in SU5416+hypoxia mice and monocrotaline rats.

• Why it matters: Maladaptive vascular remodeling in pulmonary hypertension is linked to limited smooth muscle–targeted therapies, and the role of lysine lactylation in PH progression is unclear.
• What they did: They profiled lactylation and proteins in hypoxic human pulmonary arterial smooth muscle cells, then tested ALDOA K42 using site-specific mutant virus and smooth muscle–inducible ALDOA knockout mice in SU5416+hypoxia and monocrotaline models.
• The result: ALDOA K42 lactylation enhanced ALDOA binding to γ-actin, promoting F-actin polymerization and YAP activation via LATS1 inhibition; ALDOA knockout or K42R reconstitution reduced F-actin/YAP signaling and remodeling, and β-alanine or raltegravir similarly ameliorated disease in mouse and rat models.

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