Zhao Huixian, Wang Zhixin, Wang Haijiu
Department of Hepatopancreatobiliary Surgery, the Affiliated Hospital of Qinghai University, China; Qinghai Research Key Laboratory for Echinococcosis, China; Qinghai Province Women and Children's hospital, China.
Department of Hepatopancreatobiliary Surgery, the Affiliated Hospital of Qinghai University, China; Qinghai Research Key Laboratory for Echinococcosis, China.
Pathol Res Pract. 2025 Jun;270:155996. doi: 10.1016/j.prp.2025.155996. Epub 2025 May 6.
This paper focuses on the mechanism underlying nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and subsequent hepatocyte ferroptosis. Iron is a pivotal trace element, but excessive iron deposition can lead to liver injury. Ferroptosis is a recognized, iron-dependent mode of programmed cell death that plays an important role in various liver diseases. NCOA4 is a key molecule mediating the selective autophagic degradation of ferritin. It affects ferroptosis by regulating intracellular free iron levels. NCOA4 expression is regulated by various factors, including cellular iron levels and oxidative stress. It was demonstrated that inhibition of NCOA4 can reduce iron-mediated cell death and mitigate liver damage, suggesting that NCOA4 may be a potential target for the prevention and treatment of liver diseases. Further in-depth studies of the molecular mechanism of NCOA4-mediated ferritinophagy and its relationship with iron-induced cell death can provide novel ideas for the diagnosis and treatment of liver diseases. The deficiency or abnormal expression of NCOA4 is closely associated with ferroptosis in a variety of liver diseases, including non-alcoholic fatty liver disease, alcoholic liver disease, drug-induced liver injury, and liver fibrosis. Future studies should focus on elucidating the dynamic changes in the NCOA4 regulatory network during specific pathological processes. This strategy can lay the foundation for drug development.
本文聚焦于核受体辅激活因子4（NCOA4）介导的铁蛋白自噬及随后的肝细胞铁死亡的潜在机制。铁是一种关键的微量元素，但过量的铁沉积会导致肝损伤。铁死亡是一种公认的、铁依赖性的程序性细胞死亡方式，在各种肝脏疾病中起重要作用。NCOA4是介导铁蛋白选择性自噬降解的关键分子。它通过调节细胞内游离铁水平影响铁死亡。NCOA4的表达受多种因素调控，包括细胞铁水平和氧化应激。研究表明，抑制NCOA4可减少铁介导的细胞死亡并减轻肝损伤，这表明NCOA4可能是预防和治疗肝脏疾病的潜在靶点。对NCOA4介导的铁蛋白自噬分子机制及其与铁诱导的细胞死亡关系的进一步深入研究可为肝脏疾病的诊断和治疗提供新思路。NCOA4的缺乏或异常表达与多种肝脏疾病（包括非酒精性脂肪性肝病、酒精性肝病、药物性肝损伤和肝纤维化）中的铁死亡密切相关。未来的研究应聚焦于阐明特定病理过程中NCOA4调控网络的动态变化。这一策略可为药物研发奠定基础。
