Iron is a mineral essential for blood production and a variety of critical cellular functions. Altered iron metabolism has been increasingly observed in many diseases and disorders, but a comprehensive and mechanistic understanding of the cellular impact of impaired iron metabolism is still lacking. We examined the effects of iron overload or iron deficiency on cellular stress responses and autophagy which collectively regulate cell homeostasis and survival. Acute iron loading led to increased mitochondrial ROS (mtROS) production and damage, lipid peroxidation, impaired autophagic flux, and ferroptosis. Iron-induced mtROS overproduction is the mechanism of increased lipid peroxidation, impaired autophagy, and the induction of ferroptosis. Iron excess-induced ferroptosis was cell-type dependent and regulated by activating transcription factor 4 (ATF4). Upregulation of ATF4 mitigated iron-induced autophagic dysfunction and ferroptosis, whereas silencing of ATF4 expression impaired autophagy and resulted in increased mtROS production and ferroptosis. Employing autophagy-deficient hepatocytes and different autophagy inhibitors, we further showed that autophagic impairment sensitized cells to iron-induced ferroptosis. In contrast, iron deficiency activated the endoplasmic reticulum (ER) stress response, decreased autophagy, and induced apoptosis. Decreased autophagy associated with iron deficiency was due to ER stress, as reduction of ER stress by 4-phenylbutyric acid (4-PBA) improved autophagic flux. The mechanism of decreased autophagy in iron deficiency is a disruption in lysosomal biogenesis due to impaired posttranslational maturation of lysosomal membrane proteins. In conclusion, iron excess and iron deficiency cause different forms of cell stress and death in part through the common mechanism of impaired autophagic function.

铁是血液生成和各种关键细胞功能所必需的矿物质。在许多疾病和病症中越来越多地观察到铁代谢的改变，但仍然缺乏对铁代谢受损对细胞影响的全面和机制的了解。我们研究了铁过载或铁缺乏对细胞应激反应和自噬的影响，它们共同调节细胞稳态和存活。急性铁负荷导致线粒体活性氧 (mtROS) 产生增加和损伤、脂质过氧化、自噬通量受损和铁死亡。铁诱导的 mtROS 过量产生是脂质过氧化增加、自噬受损和诱导铁死亡的机制。铁过量诱导的铁死亡具有细胞类型依赖性，并通过激活转录因子 4 (ATF4) 进行调节。ATF4 的上调可减轻铁诱导的自噬功能障碍和铁死亡，而 ATF4 表达的沉默会损害自噬并导致 mtROS 产生增加和铁死亡。利用自噬缺陷的肝细胞和不同的自噬抑制剂，我们进一步表明自噬损伤使细胞对铁诱导的铁死亡敏感。相反，缺铁会激活内质网（ER）应激反应，减少自噬并诱导细胞凋亡。与缺铁相关的自噬减少是由于内质网应激所致，因为 4-苯基丁酸 (4-PBA) 减少内质网应激可改善自噬通量。缺铁时自噬减少的机制是由于溶酶体膜蛋白翻译后成熟受损而导致溶酶体生物发生的破坏。总之，铁过量和铁缺乏会部分通过自噬功能受损的共同机制导致不同形式的细胞应激和死亡。