PDF(Pubmed)
Abstract：
Ferroptosis, a regulated cell death pathway driven by accumulation of phospholipid peroxides, has been challenging to identify in physiological conditions owing to the lack of a specific marker. Here, we identify hyperoxidized peroxiredoxin 3 (PRDX3) as a marker for ferroptosis both in vitro and in vivo. During ferroptosis, mitochondrial lipid peroxides trigger PRDX3 hyperoxidation, a posttranslational modification that converts a Cys thiol to sulfinic or sulfonic acid. Once hyperoxidized, PRDX3 translocates from mitochondria to plasma membranes, where it inhibits cystine uptake, thereby causing ferroptosis. Applying hyperoxidized PRDX3 as a marker, we determined that ferroptosis is responsible for death of hepatocytes in mouse models of both alcoholic and nonalcoholic fatty liver diseases, the most prevalent chronic liver disorders. Our study highlights the importance of ferroptosis in pathophysiological conditions and opens the possibility to treat these liver diseases with drugs that inhibit ferroptosis.
摘要：
Ferroptosis,由磷脂过氧化物积累驱动的调节细胞死亡途径，由于缺乏特定的标记，在生理条件下进行鉴定一直具有挑战性。这里,我们在体外和体内都确定了高氧化过氧化物氧还蛋白3（PRDX3）作为铁凋亡的标志物。在铁死亡期间，线粒体脂质过氧化物引发PRDX3过度氧化，将Cys硫醇转化为亚磺酸或磺酸的翻译后修饰。一旦过度氧化，PRDX3从线粒体转移到质膜，抑制胱氨酸的摄取,从而导致铁中毒。应用高氧化PRDX3作为标记，我们确定，在酒精性和非酒精性脂肪性肝病小鼠模型中，铁死亡是肝细胞死亡的原因，最常见的慢性肝脏疾病。我们的研究强调了铁性凋亡在病理生理条件下的重要性，并开辟了用抑制铁性凋亡的药物治疗这些肝脏疾病的可能性。
