Department of Medical Biochemistry, Faculty of Medicine, Tanta University, Tanta, Egypt.
Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Benha University, Toukh, Egypt.
FASEB J. 2024 Jul 31;38(14):e23816. doi: 10.1096/fj.202400254RRR.
Acetaminophen (APAP) is one of the most clinically relevant medications associated with acute liver damage. A prolific deal of research validated the hepatoprotective effect of empagliflozin (EMPA); however, its effect on APAP-induced hepatotoxicity has still not been investigated. In this study, the prospective hepatoprotective impact of EMPA against APAP-induced hepatotoxicity was investigated. Twenty-eight Balb-C mice were assigned to four groups: control, APAP, EMPA10/APAP, and EMPA25/APAP. At the end of the experiment, serum hepatotoxicity biomarkers, MDA level, and GSH content were estimated. Hepatic mitofusin-2 (MFN2), optic atrophy 1 (OPA1), dynamin-related protein 1 (Drp1), and mitochondrial fission 1 protein (FIS1) were immunoassayed. PGC-1α, cGAS, and STING mRNA expression were assessed by real-time PCR. Histopathological changes and immunohistochemistry of INF-β, p-NF-κB, and iNOS were evaluated. APAP treatment caused significant hepatic functional impairment and increased hepatic MDA levels, as well as a concomitant decrease in GSH content. Marked elevation in Drp1 and FIS1 levels, INF-ß, p-NF-κB, and iNOS immunoreactivity, and reduction in MFN2 and OPA1 levels in the APAP-injected group, PGC-1α downregulation, and high expression of cGAS and STING were also documented. EMPA effectively ameliorated APAP-generated structural and functional changes in the liver, restored redox homeostasis and mitochondrial dynamics balance, and enhanced mitochondrial biogenesis, remarkably diminished hepatic expression of cGAS and STING, and elicited a reduction in hepatic inflammation. Moreover, the computational modeling data support the interaction of APAP with antioxidant system-related proteins as well as the interactions of EMPA against Drp1, cGAS, IKKA, and iNOS proteins. Our findings demonstrated for the first time that EMPA has an ameliorative impact against APAP-induced hepatotoxicity in mice via modulation of mitochondrial dynamics, biogenesis, and cGAS/STING-dependent inflammation. Thus, this study concluded that EMPA could be a promising therapeutic modality for acute liver toxicity.
对乙酰氨基酚（APAP）是与急性肝损伤相关的最具临床意义的药物之一。大量研究证实了恩格列净（EMPA）的肝保护作用；然而，其对 APAP 诱导的肝毒性的影响仍未被研究。在这项研究中，研究了 EMPA 对 APAP 诱导的肝毒性的潜在保护作用。将 28 只 Balb-C 小鼠分为四组：对照组、APAP 组、EMPA10/APAP 组和 EMPA25/APAP 组。在实验结束时，测定血清肝毒性生物标志物、MDA 水平和 GSH 含量。免疫测定肝线粒体融合蛋白-2（MFN2）、视神经萎缩 1（OPA1）、动力相关蛋白 1（Drp1）和线粒体分裂蛋白 1（FIS1）。通过实时 PCR 评估 PGC-1α、cGAS 和 STING 的 mRNA 表达。评估 INF-β、p-NF-κB 和 iNOS 的组织病理学变化和免疫组化。APAP 处理导致肝功能明显受损，肝 MDA 水平升高，同时 GSH 含量降低。注射 APAP 组的 Drp1 和 FIS1 水平显著升高，INF-β、p-NF-κB 和 iNOS 免疫反应性升高，MFN2 和 OPA1 水平降低，PGC-1α 下调，cGAS 和 STING 高表达。EMPA 可有效改善 APAP 引起的肝结构和功能变化，恢复氧化还原平衡和线粒体动力学平衡，增强线粒体生物发生，显著降低肝 cGAS 和 STING 表达，减少肝炎症。此外，计算建模数据支持 APAP 与抗氧化系统相关蛋白的相互作用以及 EMPA 对抗 Drp1、cGAS、IKKA 和 iNOS 蛋白的相互作用。我们的研究结果首次表明，EMPA 通过调节线粒体动力学、生物发生和 cGAS/STING 依赖性炎症，对小鼠的 APAP 诱导的肝毒性具有改善作用。因此，本研究得出结论，EMPA 可能是一种有前途的急性肝毒性治疗方法。
