Acetate controls endothelial-to-mesenchymal transition.

Area of Science:

• Molecular biology
• Cellular biology
• Vascular biology

Background:

• Endothelial-to-mesenchymal transition (EndMT) is implicated in chronic vascular and fibrotic diseases.
• EndMT involves a positive feedback loop with transforming growth factor-beta (TGF-β) signaling, but its molecular drivers are unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying TGF-β-driven EndMT induction and persistence.
• To identify novel therapeutic targets for chronic vascular diseases.

Main Methods:

• Investigated metabolic alterations in endothelial cells during EndMT.
• Analyzed the role of acetate metabolism, PDK4, ACSS2, and acetylation of TGF-β signaling components (ALK5, SMADs).

Main Results:

• TGF-β-driven EndMT is underpinned by metabolic reprogramming, specifically atypical acetate production from glucose.
• EndMT induction suppresses PDK4, increasing ACSS2-dependent Ac-CoA synthesis.
• Elevated Ac-CoA acetylates ALK5 and SMADs, stabilizing TGF-β signaling.

Conclusions:

• Metabolic modulation, particularly acetate production and utilization via ACSS2, is crucial for EndMT persistence.
• ACSS2 represents a potential therapeutic target for treating chronic vascular diseases driven by EndMT.