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<p>This study evaluates the protective potential of Fondaparinux (Fond), a selective antithrombin-mediated Factor Xa inhibitor, in methotrexate-induced hepatotoxicity. The work explores its ability to correct coagulation imbalance, improve endothelial function, and attenuate oxidative and inflammatory cascades (TLR4/NLRP3, NF-κB p65/IL-1β/MCP-1). Animals were allocated into 4 groups. A control group was given distilled water via the intraperitoneal route (i.p.); an MTX group was given a single intraperitoneal injection of MTX (20 mg/kg) on the seventh experimental day; and two groups received prior prophylactic administration of Fondaparinux (at doses of 5 or 10 mg/kg, intraperitoneally) throughout seven consecutive days before as well as for an additional four-day period following MTX administration. MTX significantly elevated hepatic injury markers (AST, ALT, ALP), induced oxidative stress with depleted antioxidants (SOD, GSH), and activated TLR4/NLRP3 signaling, resulting in upregulation of inflammatory mediators&#xa0;(TNF-α, NF-κB p65, IL-18, IL-1β, MCP-1, caspase-1, iNOS, ICAM-1, MPO) and suppression of IL-10 (<i>p</i> &lt; 0.05). Endothelial dysfunction was evidenced by reduced eNOS. MTX also triggered marked coagulation disturbances, including enhanced Factor Xa–dependent thrombin generation, increased tissue factor, fibrin deposition, and elevated PAI-1. Mitochondrial apoptotic signaling was promoted, as indicated by elevated expression of cytochrome c along with induced caspase-3 and caspase-9 activation&#xa0;. Histologically, MTX caused extensive hepatic damage characterized by periportal fibrosis, inflammatory infiltration, bile duct proliferation, hepatocellular necrosis, vacuolation, and vascular congestion. Fondaparinux pretreatment dose-dependently restored hemostatic balance, improved endothelial function, suppressed oxidative and inflammatory responses, attenuated apoptosis, and markedly ameliorated histopathological alterations. Fondaparinux limits methotrexate-associated liver damage through inhibition of Factor Xa–dependent coagulation pathways while providing antioxidant, anti-inflammatory, anti-apoptotic, and hepatoprotective actions.</p>

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Fondaparinux attenuates methotrexate-induced hepatotoxicity by regulating coagulation, endothelial dysfunction, and inflammatory signaling via the TLR4/NLRP3 and NF-κB/IL-1β/MCP-1 pathways

  • 期刊论文

  • 发表日期：

    2026年5月9日

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  • Asmaa Saleh,
  • Nahed A. Raslan,
  • Heba Mohammed Refat M. Selim,
  • Ahmed Mohamed Farghly,
  • Abdel-Gawad S. Shalkami,
  • Mohamed Fathy Mohamed Sallam,
  • Shaza M. Elhusseiny,
  • Saad Ali S. Aljohani,
  • Manar Seleem Fouda,
  • Mohammed Hegazy Hassan Ali,
  • Alaa A. A Abd allatif,
  • Mohamed Fathy AbdElhamid Mohamed,
  • Safaa M. Hanafy,
  • Amany F. Mohamed,
  • Amina Ibrahim Badawy,
  • Somia Mokabel Mohamed,
  • Asmaa Magdy Elashrey,
  • Sara Nagdy Mahmoud Mousa,
  • Ahmed M. El-Dessouki

摘要

This study evaluates the protective potential of Fondaparinux (Fond), a selective antithrombin-mediated Factor Xa inhibitor, in methotrexate-induced hepatotoxicity. The work explores its ability to correct coagulation imbalance, improve endothelial function, and attenuate oxidative and inflammatory cascades (TLR4/NLRP3, NF-κB p65/IL-1β/MCP-1). Animals were allocated into 4 groups. A control group was given distilled water via the intraperitoneal route (i.p.); an MTX group was given a single intraperitoneal injection of MTX (20 mg/kg) on the seventh experimental day; and two groups received prior prophylactic administration of Fondaparinux (at doses of 5 or 10 mg/kg, intraperitoneally) throughout seven consecutive days before as well as for an additional four-day period following MTX administration. MTX significantly elevated hepatic injury markers (AST, ALT, ALP), induced oxidative stress with depleted antioxidants (SOD, GSH), and activated TLR4/NLRP3 signaling, resulting in upregulation of inflammatory mediators (TNF-α, NF-κB p65, IL-18, IL-1β, MCP-1, caspase-1, iNOS, ICAM-1, MPO) and suppression of IL-10 (p < 0.05). Endothelial dysfunction was evidenced by reduced eNOS. MTX also triggered marked coagulation disturbances, including enhanced Factor Xa–dependent thrombin generation, increased tissue factor, fibrin deposition, and elevated PAI-1. Mitochondrial apoptotic signaling was promoted, as indicated by elevated expression of cytochrome c along with induced caspase-3 and caspase-9 activation . Histologically, MTX caused extensive hepatic damage characterized by periportal fibrosis, inflammatory infiltration, bile duct proliferation, hepatocellular necrosis, vacuolation, and vascular congestion. Fondaparinux pretreatment dose-dependently restored hemostatic balance, improved endothelial function, suppressed oxidative and inflammatory responses, attenuated apoptosis, and markedly ameliorated histopathological alterations. Fondaparinux limits methotrexate-associated liver damage through inhibition of Factor Xa–dependent coagulation pathways while providing antioxidant, anti-inflammatory, anti-apoptotic, and hepatoprotective actions.