ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Gastrointestinal and Hepatic Pharmacology
This article is part of the Research TopicEmerging Talents in Frontiers in Pharmacology: Gastrointestinal and Hepatic Pharmacology 2025View all 6 articles
Disrupting Cell Death: Ferroptosis & Pyroptosis Inhibition in Hepatic Ischemia-Reperfusion Injury via modulation of GPX4 and cGAS pathways by Deferoxamine and Octreotide
Provisionally accepted
- 1Department of Pharmacology, Faculty of Pharmacy, British University in Egypt, Cairo, Egypt
- 2Center for Drug Research and Development, British University in Egypt, Cairo, Beni Suef, Egypt
- 3Department of Biochemistry, Faculty of Pharmacy, British University in Egypt, Cairo, Egypt
- 4Department of Pharmacology and Toxicology, University of Sadat City, Sadat City, Egypt
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Hepatic ischemia-reperfusion injury (HIRI) is a significant complication of liver transplantation, often precipitating postoperative liver dysfunction/failure. Given the rising global prevalence of end-stage liver disease, which necessitates liver transplantation, protecting against HIRI is crucial. Here, we investigated the effects of octreotide (OCT), a pyroptosis inhibitor, and deferoxamine (DEF), a ferroptosis suppressor, individually and combined in the HIRI model. Their impact on cyclic GMP-AMP synthase/stimulator-of-interferon (cGAS/STING) genes and glutathione peroxidase 4 (GPX4) activity was explored. Male rats (n=4-5) were subjected to 30 minutes ischemia followed by 3h reperfusion and treated with OCT (75μg/kg; 30μg/kg, i.p. & 45μg/kg, s.c.), DEF (200 mg/kg, i.p.), or their combination 30 minutes prior to ischemia. DEF and the combined therapy alleviated HIRI histopathologically compared to OCT, while all treatments improved liver function. Ferroptosis suppression was noticeable with DEF and the combined regimen , likely via GPX4 activation and cyclooxygenase 2 (COX2) inhibition . All treatments displayed anti-inflammatory activity through suppressing toll-like receptor 4 (TLR4)/nuclear factor-kappa-B (NFkB) axis and pyroptosis. The combination, however, lacked anti-pyroptotic activity. These alterations paralleled cGAS downregulation, independent of STING modulation. Collectively, DEF conferred superior hepatoprotection compared to OCT, primarily due to its antioxidant and anti-inflammatory activities. Combinatorial therapy amplified the modulation of GPX4, COX2, and TLR4/NFκB without additive antipyroptotic activity.
Keywords: Liver, ferroptosis, pyroptosis, Octreotide, Deferoxamine, Ischemia-reperfusion
Received: 12 Apr 2025; Accepted: 10 Nov 2025.
Copyright: © 2025 Tawfiq, Attia, Sleem and El-Sayed. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Rasha A. Tawfiq, rasha.tawfiq@bue.edu.eg
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