Dapagliflozin attenuates methotrexate-induced hepatorenal toxicity in rats: insights into oxidative stress, inflammation, autophagy and apoptosis.

IF 4.7 2区生物学 Q3 CELL BIOLOGY

Molecular and Cellular Biochemistry Pub Date : 2026-10-01 Epub Date: 2026-09-15 DOI:10.1007/s11010-026-05724-6

Al Shaima G Abd El Salam, Nesma A Abd Elrazik

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Abstract

Methotrexate (MTX) is a potent chemotherapeutic drug used to treat various malignancies, and serious autoimmune diseases. Unfortunately, the potential liver and kidney toxicities of MTX restrict its clinical effectiveness. The present study aims to explore the protective effects of dapagliflozin (Dapa) against MTX-induced hepatorenal toxicity in a rat model. Eighteen male Sprague-Dawley rats were randomly distributed into three groups; Normal, MTX and MTX + Dapa, rats received Dapa (10 mg/kg) orally once daily for 10 days; and a single i.p. injection of MTX (20 mg/kg) on the fifth day. The Dapa ameliorated hepatorenal histopathological changes induced by MTX and modulated liver and kidney function biomarkers. Dapa significantly upregulated the expression of PPAR-γ /Nrf-2/HO-1 which in turn downregulated the expression of NF-κB in hepatic and renal sections. Also, Dapa restored hepatic and renal tissues oxidative balance via significant elevation of GSH content and lowering MDA content. Moreover, Dapa modulated beclin1/LC3 dependent autophagy and caspase-3/Bcl-2 mediated apoptosis in hepatic and renal tissues. In conclusion, Dapa showed substantial hepatorenal protection against MTX-induced hepatorenal toxicity, highlighting a new therapeutic strategy in MTX treatment protocols.

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达格列净减轻甲氨蝶呤诱导的大鼠肝肾毒性：氧化应激、炎症、自噬和细胞凋亡。

甲氨蝶呤（MTX）是一种有效的化疗药物，用于治疗各种恶性肿瘤和严重的自身免疫性疾病。不幸的是，甲氨蝶呤潜在的肝脏和肾脏毒性限制了其临床疗效。本研究旨在探讨达格列净（Dapa）对甲氨蝶呤（mtx）诱导的大鼠肝肾毒性的保护作用。18只雄性Sprague-Dawley大鼠随机分为3组；正常、MTX和MTX + Dapa组大鼠口服Dapa (10 mg/kg)，每日1次，连用10 d；第5天单次静脉注射MTX （20 mg/kg）。Dapa改善了MTX引起的肝肾组织病理改变，并调节了肝肾功能生物标志物。Dapa显著上调PPAR-γ /Nrf-2/HO-1的表达，进而下调肝、肾组织中NF-κB的表达。此外，Dapa通过显著提高GSH含量和降低MDA含量来恢复肝脏和肾脏组织的氧化平衡。此外，Dapa调节beclin1/LC3依赖性自噬和caspase-3/Bcl-2介导的肝和肾组织凋亡。综上所述，Dapa对MTX诱导的肝肾毒性具有显著的肝肾保护作用，为MTX治疗方案提供了新的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular and Cellular Biochemistry 生物-细胞生物学

CiteScore

8.30

自引率

2.30%

发文量

293

审稿时长

1.7 months

期刊介绍： Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell. In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.