GSNOR reprograms nitrosylation to drive endothelial-to-mesenchymal transition and fibrotic vascular remodeling.

Endothelial cells are central regulators of tissue regeneration, yet how redox signaling governs the balance between vascular repair and fibrosis remains incompletely understood. Here, we identify S-nitrosoglutathione reductase (GSNOR), a key enzyme controlling S-nitrosoglutathione metabolism and protein S-nitrosylation, as a critical regulator of endothelial fate in idiopathic pulmonary fibrosis (IPF). GSNOR expression is markedly elevated in the pulmonary endothelium of IPF patients and correlates with disease severity, indicating disrupted S-nitrosothiol homeostasis during fibrogenesis. Genetic or pharmacologic inhibition of GSNOR, either globally or in endothelial cells, restores S-nitrosylation balance, preserves endothelial identity, and protects against fibrosis. In contrast, endothelial-specific GSNOR overexpression enhances denitrosylation, promoting endothelial-to-mesenchymal transition (EndoMT) and exacerbating fibrotic remodeling. Quantitative S-nitrosoproteomic analysis reveals that GSNOR broadly remodels S-nitrosylation networks governing extracellular matrix organization and endothelial signaling. Mechanistically, reduced high mobility group box 1 (HMGB1) Cysteine-23 S-nitrosylation facilitates its cytoplasmic translocation and potentiates TGF-β-driven EndoMT, linking GSNOR-associated S-nitrosylation remodeling to fibrogenic endothelial reprogramming. Collectively, these findings define endothelial GSNOR as a key regulator of S-nitrosylation-dependent endothelial plasticity and fibrotic vascular remodeling.