Fxnis the gene that encodes frataxin, a small nucleus-encoded mitochondrial protein. It is crucial for iron-sulfur cluster biogenesis, which is involved in mitochondrial ATP production and iron homeostasis [1,3]. Disruptions in Fxn-related processes can lead to various disease conditions, making it an important gene for understanding cellular metabolism and disease mechanisms. Genetic models, such as mouse models, are valuable tools for studying the function of Fxn.

In Friedreich's ataxia (FRDA), almost all patients have expanded guanine-adenine-adenine (GAA) trinucleotide repeats within intron 1 of the FXN gene, resulting in frataxin deficiency [1,3]. This deficiency leads to reduced iron-sulfur cluster biogenesis, elevated mitochondrial iron, and oxidative stress [3]. In addition, FXN has been found to be a regulator of ferroptosis. In ovarian cancer stem-like cells, high FXN levels confer ferroptosis resistance, while FXN knockdown reduces stemness, increases ROS generation, and attenuates cell viability [2]. In SH-SY5Y cells injured by L-glutamate, overexpression of FXN mitigates mitochondrial dysfunction and lipid metabolic dysregulation associated with ferroptosis [4]. In a FXN-deficient mouse model, impairment of lipolysis in white adipocytes is an early event that may lead to insulin resistance later in life [5].

In conclusion, Fxn plays essential roles in iron-sulfur cluster biogenesis, mitochondrial function, and the regulation of ferroptosis. Mouse models of Fxn deficiency have provided valuable insights into its role in diseases like Friedreich's ataxia, as well as in metabolic and cancer-related conditions, highlighting its significance in understanding disease mechanisms and developing potential therapies.