{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T22:27:15Z","timestamp":1785450435595,"version":"3.56.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cisplatin (CIS) is a highly effective chemotherapeutic agent widely used to treat solid tumors. However, its clinical use is significantly limited by dose-dependent hepatotoxicity, characterized by hepatocellular injury and apoptosis. Despite extensive research efforts, an effective pharmacological strategy to reduce CIS-induced liver dysfunction remains elusive. Sacubitril\/valsartan (VS), an angiotensin receptor\u2013neprilysin inhibitor, has shown cytoprotective and anti-apoptotic effects in various models of organ toxicity. However, its ability to protect against CIS-induced liver damage has not been thoroughly studied. This research aimed to assess the hepatoprotective potential of VS in rat models of cisplatin-induced liver toxicity, focusing on oxidative markers including reactive oxygen species (ROS) and malondialdehyde (MDA), as well as the roles of caspase-3 inhibition and modulation of retinoid X receptor-alpha (RXR-\u03b1) in its mechanism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, adult male Wistar rats were randomly assigned to four groups: control, VS-treated, cisplatin-treated, and CIS + VS co-treated. Hepatotoxicity was induced by administering cisplatin at 8\u00a0mg\/kg via intraperitoneal injection, repeated over three cycles. Meanwhile, VS was given orally at 60\u00a0mg\/kg daily for 10 days. Liver biochemical markers, including ROS, MDA, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total protein (TP), albumin (ALB), total bilirubin (TBIL), and lactate dehydrogenase (LDH), were measured using ELISA. Liver tissue was examined histologically with hematoxylin and eosin staining, and the expression of caspase-3 and RXR-\u03b1 was evaluated through immunofluorescence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Cisplatin administration significantly increased ROS, MDA, ALT, AST, ALP, TBIL, and LDH levels, while decreasing TP and ALB, indicating severe liver dysfunction. Histopathology showed extensive hepatocellular degeneration, necrosis, and inflammation. Co-treatment with VS significantly normalized liver function tests, improved protein levels, and maintained normal liver histology. Additionally, VS markedly reduced caspase-3 immunoreactivity while increasing RXR-\u03b1 expression compared to CIS alone.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Sacubitril\/valsartan appears to protect the liver from cisplatin toxicity, primarily by inhibiting oxidative stress and apoptosis through caspase-3 suppression, and modulating RXR-\u03b1 signaling. These results provide new insights into the mechanisms involved and suggest that VS may be a promising adjunct therapy to lessen cisplatin-induced hepatotoxicity during chemotherapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1745023","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T10:19:01Z","timestamp":1770286741000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Sacubitril\/valsartan mitigates cisplatin-induced liver injury through modulation of oxidative stress, Caspase-3 activity, and RXR-\u03b1 signaling in experimental rats"],"prefix":"10.3389","volume":"17","author":[{"given":"Majed N.","family":"Alshammari","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University","place":["Buraydah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad H.","family":"Alhowail","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University","place":["Buraydah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed S.","family":"Abdel-Bakky","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University","place":["Buraydah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha A.","family":"Aldubayan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University","place":["Buraydah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"112328","DOI":"10.1016\/j.biopha.2021.112328","article-title":"The role of natural antioxidants in cisplatin-induced hepatotoxicity","volume":"144","author":"Abd Rashid","year":"2021","journal-title":"Biomed. & Pharmacother."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1887","DOI":"10.1007\/s00210-020-01896-0","article-title":"Silencing of tissue factor by antisense deoxyoligonucleotide mitigates thioacetamide-induced liver injury","volume":"393","author":"Abdel-Bakky","year":"2020","journal-title":"Naunyn-Schmiedeberg's Archives Pharmacol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"385","DOI":"10.4196\/kjpp.2021.25.5.385","article-title":"Loss of RAR-\u03b1 and RXR-\u03b1 and enhanced caspase-3-dependent apoptosis in N-acetyl-p-aminophenol-induced liver injury in mice is tissue factor dependent","volume":"25","author":"Abdel-Bakky","year":"2021","journal-title":"Korean J. 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