Ncoa4, known as Nuclear receptor coactivator 4, is a selective cargo receptor that mediates the autophagic degradation of ferritin in a process called ferritinophagy. This process is crucial for maintaining intracellular and systemic iron homeostasis, which is essential for iron-dependent physiological processes like erythropoiesis. Ncoa4-mediated ferritinophagy also has a significant impact on ferroptosis, a non-apoptotic iron-dependent form of cell death [1,2].

In Mycobacterium tuberculosis infection, Ncoa4-mediated ferritin degradation in macrophages increases iron availability for the bacteria, promoting their growth. Ncoa4 deficiency in myeloid cells expedites the clearance of Mtb infection in a murine model, indicating its role in host-pathogen interaction [3]. In high-fat-diet-fed mice, STAT3 signaling promotes cardiac injury by upregulating Ncoa4-mediated ferritinophagy and ferroptosis. Knockdown of Ncoa4 alleviates oleic acid/palmitic acid-induced ferroptosis in H9C2 cells [4]. In chondrocytes, Ncoa4 is upregulated in a JNK-JUN signaling-dependent manner. Ncoa4 overexpression promotes chondrocyte ferroptosis and extracellular matrix degradation, while knockdown inhibits these processes, and disruption of the JNK-JUN-Ncoa4 axis attenuates post-traumatic osteoarthritis development [5].

In conclusion, Ncoa4 is vital for maintaining iron homeostasis through ferritinophagy and is involved in multiple disease-related processes. The study of Ncoa4 in KO/CKO mouse models has provided insights into its role in infectious diseases like tuberculosis, cardiac diseases related to high-fat diet, and osteoarthritis, highlighting its potential as a therapeutic target.