# Lactate Promotes Endothelial-Mesenchymal Transition via Mediating Twist1 Lactylation in Hypoxic Pulmonary Hypertension

## TL;DR

Lactate promotes vascular remodeling in pulmonary hypertension by enabling a new molecular pathway involving Twist1 lactylation.

## Contribution

Discovery of a novel lactate-Twist1 lactylation-TGFB1 axis driving endothelial-mesenchymal transition in PH.

## Key findings

- Lactate exacerbates pulmonary hypertension by promoting endothelial-mesenchymal transition.
- Twist1 lactylation by lactate activates TGFB1 and Smad2 pathways, driving vascular remodeling.
- Inhibiting lactate production reduces PH severity in mouse models.

## Abstract

Elevated plasma lactate is a significant risk factor in pulmonary hypertension (PH), and endothelial-mesenchymal transition (EndoMT) is a major contributor to this pathological process, yet its specific role in driving endothelial-mesenchymal transition (EndoMT) remains unclear. Using in vivo and in vitro models, we demonstrate that modulating lactate levels critically influences PH progression. In a hypoxic PH mouse model, inhibition of lactate production ameliorated hemodynamic and vascular remodeling, whereas exogenous lactate exacerbated these pathologies. In human pulmonary arterial endothelial cells under hypoxia, lactate promoted a pro-remodeling phenotype, enhancing migration, proliferation, and EndoMT. Mechanistically, lactate induced Twist1 lactylation via enhanced association with p300/CBP, promoting its nuclear translocation. This upregulated TGFB1 transcription and activated the Smad2 pathway, thereby driving EndoMT—an effect abolished by Twist1 knockdown. Our findings reveal a previously unrecognized lactate-Twist1 lactylation-TGFB1 axis that promotes vascular remodeling in PH, identifying novel therapeutic targets.