Ncoa4, or Nuclear receptor coactivator 4, is a selective cargo receptor that mediates ferritinophagy, the autophagic degradation of ferritin, the cytosolic iron storage complex. This process is crucial for maintaining intracellular and systemic iron homeostasis, thus influencing iron-dependent physiological processes like erythropoiesis. It is also associated with the regulation of ferroptosis, a non-apoptotic iron-dependent form of cell death [1,2,6]. Genetic models, such as KO or CKO mouse models, can be valuable in further understanding its functions.

In a murine model, NCOA4 deficiency in myeloid cells expedited the clearance of Mycobacterium tuberculosis infection, indicating that Mtb hijacks host NCOA4-dependent ferritinophagy to enhance its intracellular growth [3]. In high-fat-diet fed mice, knockdown of NCOA4 by SiRNA mitigated iron overload, lipid peroxidation, and cell death, suggesting that NCOA4-mediated ferritinophagy is required for high-fat-diet-induced ferroptosis [4]. Also, knockdown of Ncoa4 in chondrocytes inhibited IL-1β-induced ferroptosis and extracellular matrix degradation, while overexpression of NCOA4 promoted these effects in post-traumatic OA mice [5].

In conclusion, Ncoa4 plays essential roles in maintaining iron homeostasis and regulating ferroptosis through ferritinophagy. The use of Ncoa4 KO/CKO mouse models has provided insights into its functions in diseases such as tuberculosis, high-fat-diet-induced cardiac injury, and osteoarthritis, highlighting its potential as a therapeutic target in these disease areas.