Oxidative Ferritin Destruction: A Key Mechanism of Iron Overload in Acetaminophen-Induced Hepatocyte Ferroptosis

作者：Kaishuo Gong, Kaiying Liang, Hui Li, Hongjun Luo, Yingtong Chen, Ke Yin, Zhixin Liu, Wenhong Luo, Zhexuan Lin · 发表于：International Journal of Molecular Sciences · 年份：2025 · DOI：10.3390/ijms26157585 · 被引用次数：4 · 研究领域：Drug Transport and Resistance Mechanisms、Drug-Induced Hepatotoxicity and Protection、Trace Elements in Health

Although acetaminophen (APAP) overdose represents the predominant cause of drug-induced acute liver failure (ALF) worldwide and has been extensively studied, the modes of cell death remain debatable and the treatment approach for APAP-induced acute liver failure is still limited. This study investigated the mechanisms of APAP hepatotoxicity in primary mouse hepatocytes (PMHs) by using integrated methods (MTT assay, HPLC analysis for glutathione (GSH), Calcein-AM for labile iron pool detection, confocal microscopy for lipid peroxidation and mitochondrial superoxide measurements, electron microscopy observation, and Western blot analysis for ferritin), focusing on the role of iron dysregulation under oxidative stress. Our results showed that 20 mM APAP treatment induced characteristic features of ferroptosis, including GSH depletion, mitochondrial dysfunction, and iron-dependent lipid peroxidation. Further results showed significant ferritin degradation and subsequent iron releasing. Iron chelator deferoxamine (DFO) and N-acetylcysteine (NAC) could alleviate APAP-induced hepatotoxicity, while autophagy inhibitors did not provide a protective effect. In vitro experiments confirmed that hydrogen peroxide directly damaged ferritin structure, leading to iron releasing, which may aggravate iron-dependent lipid peroxidation. These findings provide evidence that APAP hepatotoxicity involves a self-amplifying cycle of oxidative stress and iron-mediated oxidative damaging, with ferritin...