Chen Ziwen, Zheng Nan, Wang Fuwei, Zhou Qiong, Chen Zihao, Xie Lihua, Sun Qiang, Li Li, Li Baohong
Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, The Affiliated Dongguan Songshan Lake Central Hospital, School of Pharmacy, Guangdong Medical University, Dongguan, China.
Dongguan Key Laboratory of Traditional Chinese Medicine and New Pharmaceutical Development, The Affiliated Dongguan Songshan Lake Central Hospital, School of Pharmacy, Guangdong Medical University, Dongguan, China.
Brain Res. 2025 Mar 1;1850:149340. doi: 10.1016/j.brainres.2024.149340. Epub 2024 Nov 23.
Iron is a crucial mineral element within human cells, serving as a pivotal cofactor for diverse biological enzymes. Ferritin plays a crucial role in maintaining iron homeostasis within the body through its ability to sequester and release iron. Ferritinophagy is a selective autophagic process in cells that specifically facilitates the degradation of ferritin and subsequent release of free iron, thereby regulating intracellular iron homeostasis. The nuclear receptor coactivator 4 (NCOA4) serves as a pivotal regulator in the entire process of ferritinophagy, facilitating its binding to ferritin and subsequent delivering to lysosomes for degradation, thereby enabling the release of free iron. The free iron ions within the cell undergo catalysis through the Fenton reaction, resulting in a substantial generation of reactive oxygen species (ROS). This process induces lipid peroxidation, thereby stimulating a cascade leading to cellular tissue damage and subsequent initiation of ferroptosis. Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration of emotional memory and cognitive function, accompanied by mental and behavioral aberrations. The pathology of the disease is characterized by aberrant deposition of amyloid β-protein (Aβ) and hyperphosphorylated tau protein. It has been observed that evident iron metabolism disorders and accumulation of lipid peroxides occur in AD, indicating a significant impact of ferritinophagy and ferroptosis on the pathogenesis and progression of AD. This article elucidates the process and mechanism of ferritinophagy and ferroptosis, investigating their implications in AD to identify novel targets for therapeutic intervention.
铁是人体细胞内一种关键的矿物质元素，是多种生物酶的关键辅助因子。铁蛋白通过螯合和释放铁的能力，在维持体内铁稳态方面发挥着关键作用。铁蛋白自噬是细胞内一种选择性自噬过程，它特异性地促进铁蛋白的降解及随后游离铁的释放，从而调节细胞内铁稳态。核受体辅激活因子4（NCOA4）在铁蛋白自噬的整个过程中起关键调节作用，促进其与铁蛋白结合并随后转运至溶酶体进行降解，从而使游离铁得以释放。细胞内的游离铁离子通过芬顿反应发生催化作用，导致大量活性氧（ROS）生成。这一过程诱导脂质过氧化，进而引发一系列反应，导致细胞组织损伤并随后引发铁死亡。阿尔茨海默病（AD）是一种神经退行性疾病，其特征为情感记忆和认知功能逐渐衰退，伴有精神和行为异常。该疾病的病理学特征是淀粉样β蛋白（Aβ）异常沉积和tau蛋白过度磷酸化。据观察，AD中存在明显的铁代谢紊乱和脂质过氧化物积累，这表明铁蛋白自噬和铁死亡对AD的发病机制和进展有重大影响。本文阐明了铁蛋白自噬和铁死亡的过程及机制，研究它们在AD中的意义，以确定治疗干预的新靶点。
