G6pdN126D Variant Increases the Risk of Developing VEGFR (Vascular Endothelial Growth Factor Receptor) Blocker-Induced Pulmonary Vascular Disease

Authors: Christina Signoretti, Shun Matsumura, Samuel Fatehi, Melinee D'Silva, Rajamma Mathew, Francesca Cendali, Angelo D'Alessandro, S M Shafiqul Alam, Victor Garcia, Joseph M Miano, Sachin A Gupte

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This study examined the role of an X-linked G6PD variant (N126D), prevalent in individuals of African ancestry, in vascular endothelial growth factor receptor blocker–induced pulmonary hypertension. Using CRISPR-engineered rats, we found that the G6PDN126D variant exacerbated pulmonary hypertension following sugen-5416 treatment, marked by increased right ventricular pressure, pulmonary artery remodeling, oxidative stress, disrupted nitric oxide signaling, inflammation, thrombosis, and enhanced inositol triphosphate–Ca²⁺ signaling. These findings suggest that this G6PD variant increases susceptibility to drug-induced pulmonary hypertension and highlight metabolic reprogramming as a key driver of vascular pathology.

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