FDX1, also known as adrenodoxin, is a small mitochondrial protein and an iron-sulfur (Fe-S) cluster protein. It serves as an essential electron donor in multiple cellular processes. FDX1 is involved in pathways such as steroidogenesis, heme a and lipoyl cofactor biosyntheses, and is crucial for the biogenesis of mitochondrial cytochrome c oxidase (CcO), a key enzyme in the mitochondrial respiratory chain [4,6]. It also plays a significant role in copper-related cell death (cuproptosis) and the regulation of cellular protein lipoylation, which is important for the TCA cycle function [2,3,7]. Genetic models, such as gene knockout (KO) mouse models, can be used to further explore its functions.

In hepatocellular carcinoma (HCC), FDX1 down-regulation promotes cell proliferation, invasion, and metastasis both in vitro and in vivo. It activates mitophagy and the PI3K/AKT signaling pathway by inducing ROS production, and low FDX1 expression is associated with shorter survival in HCC patients [1]. In clear cell renal cell carcinoma (ccRCC), FDX1 acts as a tumor suppressor, and the miR-21-5p/FDX1 axis is associated with immune cell infiltration in the tumor microenvironment [5]. In thyroid cancer, FDX1 promotes cuprotosis by regulating the lipoylation of DLAT, thus inhibiting the cancer's malignant progression [7].

In conclusion, FDX1 is essential for various mitochondrial-related functions and plays a crucial role in the development of multiple cancers. Studies using KO or other loss-of-function models have significantly enhanced our understanding of FDX1's role in specific disease conditions, providing potential therapeutic targets for these diseases.