Gao Liyuan, Chang Xiaoyan, Han Yi, Li Jian, Meng Ying, Yang Xiang, Jiang Zhitao
Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China.
Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China.
Int Immunopharmacol. 2025 May 8;154:114490. doi: 10.1016/j.intimp.2025.114490. Epub 2025 Mar 29.
Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI) and can progress to acute liver failure (ALF). Hepatocyte death is widely recognized as the central event in APAP-induced liver injury; however, the underlying mechanisms are complex and not yet fully elucidated. Ferroptosis, a recently identified form of programmed cell death characterized by glutathione (GSH) depletion and disruption of cellular redox homeostasis, shares key features with APAP-induced hepatotoxicity. This study aimed to investigate the role of ferroptosis in APAP-induced liver injury and to explore potential therapeutic targets.
C57BL/6 mice were administered APAP to evaluate ferroptosis and hepatic injury in vivo through histological and biochemical analyses. A range of molecular techniques, along with the establishment of stable cell lines, were employed to elucidate the underlying mechanisms in vitro.
We demonstrated that APAP disrupts iron homeostasis and promotes hepatocyte ferroptosis. OTULIN, a deubiquitinase involved in linear ubiquitination, was found to regulate the ubiquitination modification of NCOA4, leading to NCOA4 depletion and FTH1 accumulation. This process enhanced the resistance and adaptability of hepatocytes to APAP-induced damage.
Our findings reveal that OTULIN modulates the NCOA4-FTH1 complex to protect against APAP-induced hepatocyte ferroptosis. Targeted upregulation of OTULIN in hepatocytes may represent a promising therapeutic strategy for APAP-induced DILI.
对乙酰氨基酚（APAP）过量是药物性肝损伤（DILI）的主要原因，可进展为急性肝衰竭（ALF）。肝细胞死亡被广泛认为是APAP诱导的肝损伤的核心事件；然而，其潜在机制复杂且尚未完全阐明。铁死亡是最近发现的一种程序性细胞死亡形式，其特征是谷胱甘肽（GSH）耗竭和细胞氧化还原稳态破坏，与APAP诱导的肝毒性具有关键特征。本研究旨在探讨铁死亡在APAP诱导的肝损伤中的作用，并探索潜在的治疗靶点。
给C57BL/6小鼠注射APAP，通过组织学和生化分析评估体内铁死亡和肝损伤。采用一系列分子技术以及建立稳定细胞系来阐明体外潜在机制。
我们证明APAP破坏铁稳态并促进肝细胞铁死亡。OTULIN是一种参与线性泛素化的去泛素酶，被发现可调节NCOA4的泛素化修饰，导致NCOA4耗竭和FTH1积累。这一过程增强了肝细胞对APAP诱导损伤的抵抗力和适应性。
我们的研究结果表明，OTULIN调节NCOA4-FTH1复合物以保护肝细胞免受APAP诱导的铁死亡。在肝细胞中靶向上调OTULIN可能是治疗APAP诱导的DILI的一种有前景的治疗策略。
