Ambrisentan ameliorates methotrexate nephrotoxicity through modulation of RhoA/ROCK and PI3K/MDM2-associated signaling: network pharmacology-guided discovery and in vivo confirmation
6 affiliations
- 1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ahram Canadian University
- 2Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University
- 3Department of Pharmacology and Toxicology, Faculty of Pharmacy, Misr International University
- 4Department of Histology and Cell Biology, Faculty of Medicine for Girls, Al-Azhar University
- 5Basic Health Sciences Department, College of Medicine, Princess Nourah bint Abdulrahman University
- 6Pharmacology & Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC)
Abstract
Introduction: Methotrexate (MTX) is a potent antineoplastic agent; however, its clinical application is frequently limited by nephrotoxicity, which may result in treatment interruption. Previous evidence indicates that MTX can promote endothelin-1 (ET-1)-associated renal injury. Therefore, this study investigated whether blocking ET-1 receptors with Ambrisentan (AMB) could alleviate MTX-induced acute kidney injury (AKI).
Methods: Network pharmacology analysis was performed to identify potential targets and pathways associated with AMB and MTX-induced AKI. For In-vivo validation, twenty-four rats were divided into four groups: control, AMB, MTX, and MTX+AMB.
Results and Discussion: Network pharmacology identified 102 overlapping targets between AMB and MTX-induced AKI, with 20 hub genes identified through protein–protein interaction network analysis, highlighting PPAR-γ as a key target. KEGG pathway enrichment revealed the involvement of RhoA/ROCK and PI3K-associated signaling pathways, in correlation with inflammatory and apoptotic markers. Experimentally, AMB co-treatment improved renal function parameters and histopathological alterations, restored oxidative balance, and attenuated MTX-induced inflammatory and apoptotic responses, including ICAM-1, NF-κB, RhoA/ROCK, Bax, Caspase-3 and p53. Furthermore, AMB restored the expression of PPAR-γ, PI3K, MDM2, and Bcl-2, suggesting the involvement of PI3K/MDM2-associated signaling alterations in AMB-mediated nephroprotection. In conclusion, AMB may mitigate MTX-induced nephrotoxicity through modulation of oxidative stress, inflammation, and apoptosis. Further studies are required to evaluate its effects on MTX pharmacokinetics, renal elimination, antineoplastic efficacy, and therapeutic potential in established MTX-induced AKI.
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BibTeX
@article{baraka2026ambrisentan,
title = {{Ambrisentan ameliorates methotrexate nephrotoxicity through modulation of RhoA/ROCK and PI3K/MDM2-associated signaling: network pharmacology-guided discovery and in vivo confirmation}},
author = {Sara A. Baraka and Nermin Eissa and Marwa M. Nagib and Asmaa M. Elmaghraby and Azza A. K. El-Sheikh and Samar F. Darwish},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1976309},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1976309/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Ambrisentan ameliorates methotrexate nephrotoxicity through modulation of RhoA/ROCK and PI3K/MDM2-associated signaling: network pharmacology-guided discovery and in vivo confirmation
AU - Sara A. Baraka
AU - Nermin Eissa
AU - Marwa M. Nagib
AU - Asmaa M. Elmaghraby
AU - Azza A. K. El-Sheikh
AU - Samar F. Darwish
PY - 2026
DA - 2026/10/29
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1976309
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1976309/full
AB - Introduction: Methotrexate (MTX) is a potent antineoplastic agent; however, its clinical application is frequently limited by nephrotoxicity, which may result in treatment interruption. Previous evidence indicates that MTX can promote endothelin-1 (ET-1)-associated renal injury. Therefore, this study investigated whether blocking ET-1 receptors with Ambrisentan (AMB) could alleviate MTX-induced acute kidney injury (AKI). Methods: Network pharmacology analysis was performed to identify potential targets and pathways associated with AMB and MTX-induced AKI. For In-vivo validation, twenty-four rats were divided into four groups: control, AMB, MTX, and MTX+AMB. Results and Discussion: Network pharmacology identified 102 overlapping targets between AMB and MTX-induced AKI, with 20 hub genes identified through protein–protein interaction network analysis, highlighting PPAR-γ as a key target. KEGG pathway enrichment revealed the involvement of RhoA/ROCK and PI3K-associated signaling pathways, in correlation with inflammatory and apoptotic markers. Experimentally, AMB co-treatment improved renal function parameters and histopathological alterations, restored oxidative balance, and attenuated MTX-induced inflammatory and apoptotic responses, including ICAM-1, NF-κB, RhoA/ROCK, Bax, Caspase-3 and p53. Furthermore, AMB restored the expression of PPAR-γ, PI3K, MDM2, and Bcl-2, suggesting the involvement of PI3K/MDM2-associated signaling alterations in AMB-mediated nephroprotection. In conclusion, AMB may mitigate MTX-induced nephrotoxicity through modulation of oxidative stress, inflammation, and apoptosis. Further studies are required to evaluate its effects on MTX pharmacokinetics, renal elimination, antineoplastic efficacy, and therapeutic potential in established MTX-induced AKI.
SN - 1663-9812
ER -