Alhaddad Aisha, Mosalam Esraa M, AboShabaan Hind S, Sallam Amany Said, Mahfouz Marwa M, Elhosary Enas, Mohammed Asmaa A, Metwally Ebtehal M, Shaldam Moataz A, Ghoneim Mai El-Sayed
Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, Medina 42353, Saudi Arabia.
Biochemistry Department, Faculty of Pharmacy, Menoufia University, Shebin El-Kom 32511, Menoufia, Egypt.
Pharmaceuticals (Basel). 2025 Mar 13;18(3):405. doi: 10.3390/ph18030405.
Acetaminophen (APAP)-induced acute liver injury (ALI) is increasingly becoming a public health issue with high rate of morbidity and mortality. Therefore, there is a critical demand for finding protective modalities by understanding the underlying proposed mechanisms including, but not limited to, ferroptosis and inflammation. This study seeks to investigate the possible hepatoprotective effect of empagliflozin (EMPA) against APAP-induced ALI through modulation of ferroptosis and inflammatory cascades. Mice were allocated into the following five groups: vehicle control, APAP, EMPA 10, EMPA 20 (10 and 20 mg/kg/day, respectively, P.O.), and N-acetylcysteine (NAC, hepatoprotective agent against APAP-induced ALI). The hepatic injury was detected by determining liver enzymes and by histopathological examination. Inflammation, oxidative stress, apoptosis, and ferroptosis were also evaluated. The APAP group showed an elevated level of hepatic enzymes with disrupted hepatic architecture. This toxicity was promoted by inflammation, oxidative stress, apoptosis, and ferroptosis, as indicated by elevated cytokines, lipid peroxidation, reduced antioxidants, increased caspase-3, decreased Bcl-2, and activation of the NF-κB/STAT3/hepcidin pathway. Pretreatment with EMPA remarkably reversed these features, which was reflected by restoration of the histoarchitecture of hepatic tissue, but the higher dose of EMPA was more efficient. APAP can induce ALI through initiation of inflammatory and oxidative conditions, which favor ferroptosis. EMPA hindered these unfavorable consequences; an outcome which indicates its anti-inflammatory, antioxidant, anti-apoptotic, and anti-ferroptotic effects. This modulatory action advocated EMPA as a potential hepatoprotective agent.
对乙酰氨基酚（APAP）诱导的急性肝损伤（ALI）正日益成为一个发病率和死亡率都很高的公共卫生问题。因此，迫切需要通过了解潜在的机制（包括但不限于铁死亡和炎症）来寻找保护方式。本研究旨在探讨恩格列净（EMPA）通过调节铁死亡和炎症级联反应对APAP诱导的ALI可能具有的肝保护作用。将小鼠分为以下五组：溶剂对照组、APAP组、EMPA 10组、EMPA 20组（分别为10和20 mg/kg/天，口服）以及N - 乙酰半胱氨酸（NAC，一种针对APAP诱导的ALI的肝保护剂）。通过测定肝酶和组织病理学检查来检测肝损伤。还评估了炎症、氧化应激、细胞凋亡和铁死亡情况。APAP组肝酶水平升高，肝结构遭到破坏。炎症、氧化应激、细胞凋亡和铁死亡促进了这种毒性，表现为细胞因子升高、脂质过氧化、抗氧化剂减少、caspase - 3增加、Bcl - 2减少以及NF - κB/STAT3/铁调素途径激活。EMPA预处理显著逆转了这些特征，这通过肝组织组织结构的恢复得以体现，但较高剂量的EMPA效果更显著。APAP可通过引发有利于铁死亡的炎症和氧化状态来诱导ALI。EMPA阻碍了这些不良后果；这一结果表明其具有抗炎、抗氧化、抗细胞凋亡和抗铁死亡作用。这种调节作用表明EMPA是一种潜在的肝保护剂。
