# NFS1 Regulates IDH2 to Attenuate Abdominal Aortic Aneurysms via Interacting With SP2

## TL;DR

This study shows that NFS1 helps prevent abdominal aortic aneurysms by regulating energy metabolism in smooth muscle cells.

## Contribution

The study reveals a novel role for NFS1 in AAA progression via its interaction with SP2 and regulation of IDH2.

## Key findings

- NFS1 is downregulated in AAA tissues and its loss promotes glycolysis in vascular smooth muscle cells.
- NFS1 acts as a cofactor for SP2 to regulate the expression of IDH2, which is critical for AAA development.
- Reduced NFS1 binding to SP2 leads to decreased IDH2 expression and worsens AAA progression.

## Abstract

Abdominal aortic aneurysm (AAA) is a life‐threatening condition with limited pharmacological therapies. The pathological progression of AAA is closely attributed to the phenotypic switching of vascular smooth muscle cells (VSMCs). NFS1 is the rate‐limiting enzyme for the synthesis of iron‐sulfur proteins, and the roles of NFS1 in AAA initiation and development have not been explored. Angiotensin II (Ang II) infusion‐induced AAA animal model with Apoe
−/− mice combined with human thoracic aorta samples are used to analyze the role of NFS1 in AAA development. Gain or loss‐of‐function studies are conducted to investigate the regulatory roles of NFS1 on SMC phenotypic switching at both cellular and animal levels. CUT&Tag is further performed for identifying the targets of NFS1 involved in AAA progression. NFS1 is downregulated in the abdominal aortic tissues from both patients and mice. Defects in NFS1 in VSMCs led to enhanced glycolysis and impaired mitochondrial function, contributing to the phenotypic transformation of VSMCs. Mechanistically, NFS1 functions as a transcriptional cofactor of SP2 for inducing the transcription of Idh2. Inhibition of IDH2 partially attenuated the protective effect of NFS1 on AAA. This study uncovers a crucial role for NFS1 in the development and progression of AAA, suggesting that NFS1 may serve as a novel therapeutic and prognostic marker for this condition.

The loss of NFS1 leads to its reduced binding with the transcription factor SP2, resulting in decreased expression of the downstream gene Idh2. This causes a shift in energy supply toward glycolysis in VSMCs, ultimately contributing to the occurrence and progression of AAA.