Abstract：
Acetaminophen (APAP), a widely used pain and fever reliever, is a major contributor to drug-induced liver injury, as its toxic metabolites such as NAPQI induce oxidative stress and hepatic necrosis. While N-acetylcysteine serves as the primary treatment for APAP-induced liver injury (AILI), its efficacy is confined to a narrow window of 8-24 h post-APAP overdose. Beyond this window, liver transplantation emerges as the final recourse, prompting ongoing research to pinpoint novel therapeutic targets aimed at enhancing AILI treatment outcomes. Nerve injury-induced protein 1 (Ninjurin1; Ninj1), initially recognized as an adhesion molecule, has been implicated in liver damage stemming from factors like TNFα and ischemia-reperfusion. Nonetheless, its role in oxidative stress-related liver diseases, including AILI, remains unexplored. In this study, we observed up-regulation of Ninj1 expression in the livers of both human DILI patients and the AILI mouse model. Through the utilization of Ninj1 null mice, hepatocyte-specific Ninj1 KO mice, and myeloid-specific Ninj1 KO mice, we unveiled that the loss of Ninj1 in hepatocytes, rather than myeloid cells, exerts alleviative effects on AILI irrespective of sex dependency. Further in vitro experiments demonstrated that Ninj1 deficiency shields hepatocytes from APAP-induced oxidative stress, mitochondrial dysfunctions, and cell death by bolstering NRF2 stability via activation of AMPKα. In summary, our findings imply that Ninj1 likely plays a role in AILI, and its deficiency confers protection against APAP-induced hepatotoxicity through the AMPKα-NRF2 pathway.
摘要：
对乙酰氨基酚(APAP),一种广泛使用的疼痛和发烧缓解剂，是药物性肝损伤的主要原因，作为其毒性代谢产物，如NAPQI诱导氧化应激和肝坏死。虽然N-乙酰半胱氨酸是APAP诱导的肝损伤（AILI）的主要治疗方法，其疗效仅限于APAP用药过量后8-24小时的狭窄窗口。在这个窗口之外，肝移植成为最后的手段，促使正在进行的研究确定旨在增强AILI治疗结果的新治疗靶点。神经损伤诱导蛋白1(Ninjurin1;Ninj1),最初被认为是粘附分子，与TNFα和缺血再灌注等因素引起的肝损伤有关。尽管如此，它在氧化应激相关的肝脏疾病中的作用，包括AILI,仍未探索。在这项研究中,我们观察到人DILI患者和AILI小鼠模型肝脏中Ninj1表达的上调。通过利用Ninj1空小鼠，肝细胞特异性Ninj1KO小鼠，和骨髓特异性Ninj1KO小鼠，我们揭示了肝细胞中Ninj1的丢失，而不是骨髓细胞，对AILI有缓解作用，与性别依赖无关。进一步的体外实验表明，Ninj1缺乏保护肝细胞免受APAP诱导的氧化应激，线粒体功能障碍,和通过激活AMPKα来增强NRF2稳定性的细胞死亡。总之,我们的发现暗示Ninj1可能在AILI中起作用，其缺乏通过AMPKα-NRF2途径赋予对APAP诱导的肝毒性的保护作用。
