Scientists uncover how YWHAZ protein fuels deadly lung vessel damage

A new study has uncovered how a protein called YWHAZ drives harmful changes in the lungs’ blood vessels. Published in Cell Death Discovery, the research highlights its role in pulmonary arterial hypertension (PAH), a severe cardiovascular condition. Scientists believe these findings could pave the way for treatments targeting metabolism to reverse dangerous vascular remodelling. The study reveals that YWHAZ levels rise sharply in remodeled pulmonary arteries from both disease models and PAH patients. Under low-oxygen conditions, the protein stabilises HIF1A, a key regulator that shifts cells toward anaerobic glycolysis. This metabolic reprogramming boosts lactate production and disrupts normal energy processes.

YWHAZ’s influence extends beyond metabolism. It alters reactive oxygen species (ROS) levels, damages mitochondrial function, and skews cellular redox balance. These changes collectively drive the thickening and stiffening of artery walls—a defining feature of PAH. Researchers found that blocking YWHAZ or its activity reverses these effects. By interrupting the YWHAZ-HIF1A-LDHA signalling pathway, they restored healthier metabolic profiles and reduced vascular remodelling. This suggests the axis acts as a critical control point for both molecular and metabolic dysfunction in diseased arteries.

The discovery positions YWHAZ as a potential therapeutic target for PAH and related cardiovascular diseases. By normalising metabolism, treatments aimed at this protein could halt or even reverse pathological remodelling. Further research may now explore how to translate these findings into clinical strategies for patients.