# NFS1 Plays a Critical Role in Regulating Ferroptosis Homeostasis

## TL;DR

NFS1 regulates ferroptosis, a type of cell death, and its function affects cancer growth and diseases like heart and neurological disorders.

## Contribution

This paper systematically reviews the molecular mechanisms of NFS1 in ferroptosis and its therapeutic potential.

## Key findings

- NFS1 maintains Fe-S cluster homeostasis and modulates pathways like ACO1/IRP1 and GPX4 to regulate ferroptosis.
- Abnormal NFS1 function increases free iron and ROS, leading to lipid peroxidation and cell death.
- NFS1 upregulation in tumors promotes resistance to ferroptosis, while downregulation in cardiomyocytes and neurons worsens ferroptosis.

## Abstract

Ferroptosis is an iron-dependent form of regulated cell death (RCD) characterized by intracellular iron homeostasis disruption and lipid peroxide accumulation. It is involved in many pathological processes, including malignant tumors, cardiovascular diseases, inflammatory diseases, and mitochondrial disorders. Cysteine desulfurase (NFS1), a key enzyme in mitochondrial iron-sulfur (Fe-S) cluster biosynthesis, participates in regulating cellular ferroptosis by maintaining Fe-S cluster homeostasis and modulating the ACO1/IRP1 axis, the Xc−–glutathione (GSH)–glutathione peroxidase 4 (GPX4) axis, and the p53/STAT signaling pathway. When the function of NFS1 is abnormal, the intracellular free iron level is elevated, followed by reactive oxygen species (ROS) accumulation and lipid peroxidation. NFS1 expression exhibits significant variation across different tissues. Upregulation of NFS1 in tumors can enhance tumor cell resistance to ferroptosis; thus, it can promote tumor growth, drug resistance, and metastatic ability. Conversely, downregulation of NFS1 in cardiomyocytes and neurons exacerbates ferroptosis and causes functional impairment. Here, we systematically review recent advances in the molecular mechanisms of NFS1-mediated ferroptosis and its role in various disease models, intending to clarify key components in the upstream regulatory network of ferroptosis and explore the application value of NFS1 as a potential therapeutic target. The review shows that NFS1 plays an important role in cellular fate regulation, which has significant clinical application potential in the treatment of cancer and interventions for neurological and cardiovascular diseases. Therefore, it can provide a new theoretical basis and research direction for subsequent mechanism research and targeted therapeutic strategy development.