Ivermectin Attenuates Methotrexate-Induced Liver Fibrosis by Reducing TGF-β and Syndecan-1 Expression
<i>Background and Objectives:</i> Methotrexate (MTX) is widely used in clinical settings but is often associated with hepatotoxic side effects, including oxidative stress, inflammation, and fibrosis. Novel therapeutic strategies are needed to mitigate MTX-induced liver injury. This study...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-06-01
|
| Series: | Medicina |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1648-9144/61/6/1036 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849705039888646144 |
|---|---|
| author | Cengiz Dibekoğlu Kubilay Kemertaş Hatice Aygun Oytun Erbaş |
| author_facet | Cengiz Dibekoğlu Kubilay Kemertaş Hatice Aygun Oytun Erbaş |
| author_sort | Cengiz Dibekoğlu |
| collection | DOAJ |
| description | <i>Background and Objectives:</i> Methotrexate (MTX) is widely used in clinical settings but is often associated with hepatotoxic side effects, including oxidative stress, inflammation, and fibrosis. Novel therapeutic strategies are needed to mitigate MTX-induced liver injury. This study aimed to evaluate the hepatoprotective effects of ivermectin in a rat model of MTX-induced hepatotoxicity. <i>Materials and Methods:</i> Thirty male Wistar albino rats were randomly divided into three groups (n = 10 per group): control (saline only), MTX (single intraperitoneal dose of 20 mg/kg MTX), and MTX + ivermectin (20 mg/kg MTX + 0.5 mg/kg/day ivermectin for 10 days). At the end of the experiment, blood and liver tissues were collected for histopathological and biochemical evaluation, including ALT, malondialdehyde (MDA), TGF-β, and syndecan-1 levels. <i>Results:</i> MTX administration significantly increased plasma and hepatic MDA, TGF-β, syndecan-1, and ALT levels, alongside histological evidence of necrosis, fibrosis, and inflammatory infiltration (<i>p</i> < 0.001 vs. control). Ivermectin treatment significantly attenuated these alterations, with reductions in MDA (both plasma and liver), TGF-β, syndecan-1, and ALT levels (<i>p</i> < 0.05–0.001 vs. MTX). Histological scoring also revealed improved liver architecture and decreased necrosis, fibrosis, and leukocyte infiltration. <i>Conclusions:</i> Ivermectin demonstrates a strong hepatoprotective effect against MTX-induced liver injury, likely through antioxidant, anti-inflammatory, antifibrotic, and endothelial-protective mechanisms. These findings support the repurposing potential of ivermectin in mitigating drug-induced hepatic damage. |
| format | Article |
| id | doaj-art-8eb76a0bb95e429995f2536f31d1cefc |
| institution | DOAJ |
| issn | 1010-660X 1648-9144 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Medicina |
| spelling | doaj-art-8eb76a0bb95e429995f2536f31d1cefc2025-08-20T03:16:34ZengMDPI AGMedicina1010-660X1648-91442025-06-01616103610.3390/medicina61061036Ivermectin Attenuates Methotrexate-Induced Liver Fibrosis by Reducing TGF-β and Syndecan-1 ExpressionCengiz Dibekoğlu0Kubilay Kemertaş1Hatice Aygun2Oytun Erbaş3Department of General Surgery, Demiroğlu Bilim University, 34394 Istanbul, TurkeyDepartment of General Surgery, Florence Nightingale Hospital, 34394 Istanbul, TurkeyDepartment of Physiology, Faculty of Medicine, Tokat Gaziosmanpaşa University, 60250 Tokat, TurkeyFaculty of Medicine, BAMER, Biruni University, 34015 Istanbul, Turkey<i>Background and Objectives:</i> Methotrexate (MTX) is widely used in clinical settings but is often associated with hepatotoxic side effects, including oxidative stress, inflammation, and fibrosis. Novel therapeutic strategies are needed to mitigate MTX-induced liver injury. This study aimed to evaluate the hepatoprotective effects of ivermectin in a rat model of MTX-induced hepatotoxicity. <i>Materials and Methods:</i> Thirty male Wistar albino rats were randomly divided into three groups (n = 10 per group): control (saline only), MTX (single intraperitoneal dose of 20 mg/kg MTX), and MTX + ivermectin (20 mg/kg MTX + 0.5 mg/kg/day ivermectin for 10 days). At the end of the experiment, blood and liver tissues were collected for histopathological and biochemical evaluation, including ALT, malondialdehyde (MDA), TGF-β, and syndecan-1 levels. <i>Results:</i> MTX administration significantly increased plasma and hepatic MDA, TGF-β, syndecan-1, and ALT levels, alongside histological evidence of necrosis, fibrosis, and inflammatory infiltration (<i>p</i> < 0.001 vs. control). Ivermectin treatment significantly attenuated these alterations, with reductions in MDA (both plasma and liver), TGF-β, syndecan-1, and ALT levels (<i>p</i> < 0.05–0.001 vs. MTX). Histological scoring also revealed improved liver architecture and decreased necrosis, fibrosis, and leukocyte infiltration. <i>Conclusions:</i> Ivermectin demonstrates a strong hepatoprotective effect against MTX-induced liver injury, likely through antioxidant, anti-inflammatory, antifibrotic, and endothelial-protective mechanisms. These findings support the repurposing potential of ivermectin in mitigating drug-induced hepatic damage.https://www.mdpi.com/1648-9144/61/6/1036ivermectinmethotrexatehepatotoxicityliver fibrosisoxidative stressTGF-β |
| spellingShingle | Cengiz Dibekoğlu Kubilay Kemertaş Hatice Aygun Oytun Erbaş Ivermectin Attenuates Methotrexate-Induced Liver Fibrosis by Reducing TGF-β and Syndecan-1 Expression Medicina ivermectin methotrexate hepatotoxicity liver fibrosis oxidative stress TGF-β |
| title | Ivermectin Attenuates Methotrexate-Induced Liver Fibrosis by Reducing TGF-β and Syndecan-1 Expression |
| title_full | Ivermectin Attenuates Methotrexate-Induced Liver Fibrosis by Reducing TGF-β and Syndecan-1 Expression |
| title_fullStr | Ivermectin Attenuates Methotrexate-Induced Liver Fibrosis by Reducing TGF-β and Syndecan-1 Expression |
| title_full_unstemmed | Ivermectin Attenuates Methotrexate-Induced Liver Fibrosis by Reducing TGF-β and Syndecan-1 Expression |
| title_short | Ivermectin Attenuates Methotrexate-Induced Liver Fibrosis by Reducing TGF-β and Syndecan-1 Expression |
| title_sort | ivermectin attenuates methotrexate induced liver fibrosis by reducing tgf β and syndecan 1 expression |
| topic | ivermectin methotrexate hepatotoxicity liver fibrosis oxidative stress TGF-β |
| url | https://www.mdpi.com/1648-9144/61/6/1036 |
| work_keys_str_mv | AT cengizdibekoglu ivermectinattenuatesmethotrexateinducedliverfibrosisbyreducingtgfbandsyndecan1expression AT kubilaykemertas ivermectinattenuatesmethotrexateinducedliverfibrosisbyreducingtgfbandsyndecan1expression AT haticeaygun ivermectinattenuatesmethotrexateinducedliverfibrosisbyreducingtgfbandsyndecan1expression AT oytunerbas ivermectinattenuatesmethotrexateinducedliverfibrosisbyreducingtgfbandsyndecan1expression |