Ncoa4, known as Nuclear receptor coactivator 4, is a selective cargo receptor. It mediates the autophagic degradation of ferritin, a cytosolic iron storage complex, in a process called ferritinophagy. This function is crucial for maintaining intracellular and systemic iron homeostasis, which is essential for iron-dependent physiological processes like erythropoiesis. Ferritinophagy regulated by Ncoa4 also impacts ferroptosis, a non-apoptotic iron-dependent cell death pathway [1,2]. Genetic models, such as KO/CKO mouse models, are valuable for studying Ncoa4's functions.

In a murine model, Ncoa4 deficiency in myeloid cells expedited the clearance of Mycobacterium tuberculosis infection, as Mtb had been shown to hijack host Ncoa4-dependent ferritinophagy to enhance its intracellular growth [3]. In high-fat-diet fed mice, knockdown of Ncoa4 alleviated oleic acid/palmitic acid-induced ferroptosis in H9C2 cells, suggesting Ncoa4-mediated ferritinophagy contributed to high-fat-diet-induced cardiac injury [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 osteoarthritis mouse models, indicating Ncoa4's role in chondrocyte ferroptosis and OA pathogenesis [5].

In conclusion, Ncoa4 is essential for maintaining iron homeostasis through ferritinophagy and has a significant impact on processes like ferroptosis. Studies using Ncoa4 KO/CKO mouse models have revealed its roles in diseases such as tuberculosis, high-fat-diet-induced cardiac injury, and osteoarthritis, providing insights into potential therapeutic targets for these conditions.

References:

1. Santana-Codina, Naiara, Gikandi, Ajami, Mancias, Joseph D. . The Role of NCOA4-Mediated Ferritinophagy in Ferroptosis. In Advances in experimental medicine and biology, 1301, 41-57. doi:10.1007/978-3-030-62026-4_4. https://pubmed.ncbi.nlm.nih.gov/34370287/

2. Santana-Codina, Naiara, Mancias, Joseph D. 2018. The Role of NCOA4-Mediated Ferritinophagy in Health and Disease. In Pharmaceuticals (Basel, Switzerland), 11, . doi:10.3390/ph11040114. https://pubmed.ncbi.nlm.nih.gov/30360520/

3. Dai, Youchao, Zhu, Chuanzhi, Xiao, Wei, Chen, Xinchun, Cai, Yi. 2023. Mycobacterium tuberculosis hijacks host TRIM21- and NCOA4-dependent ferritinophagy to enhance intracellular growth. In The Journal of clinical investigation, 133, . doi:10.1172/JCI159941. https://pubmed.ncbi.nlm.nih.gov/37066876/

4. Zhu, Mengying, Peng, Lulu, Huo, Shengqi, Lv, Jiagao, Lin, Li. 2023. STAT3 signaling promotes cardiac injury by upregulating NCOA4-mediated ferritinophagy and ferroptosis in high-fat-diet fed mice. In Free radical biology & medicine, 201, 111-125. doi:10.1016/j.freeradbiomed.2023.03.003. https://pubmed.ncbi.nlm.nih.gov/36940731/

5. Sun, Kai, Hou, Liangcai, Guo, Zhou, Zhang, Xiong, Guo, Fengjing. 2023. JNK-JUN-NCOA4 axis contributes to chondrocyte ferroptosis and aggravates osteoarthritis via ferritinophagy. In Free radical biology & medicine, 200, 87-101. doi:10.1016/j.freeradbiomed.2023.03.008. https://pubmed.ncbi.nlm.nih.gov/36907253/