The angiotensin II receptor blocker candesartan mitigates cisplatin-induced myocardial injury via suppression of TLR-4/NF-κB/IRF-3/AP-1 signaling and restoration of antioxidant defenses

Emad H M Hassanein; Omnia A M Abd El-Ghafar; Sulaiman M Alnasser; Reem S Alruhaimi; Hanan S Althagafy; Ahmed M Atwa; Ayman M Mahmoud

doi:10.1016/j.tice.2026.103452

The angiotensin II receptor blocker candesartan mitigates cisplatin-induced myocardial injury via suppression of TLR-4/NF-κB/IRF-3/AP-1 signaling and restoration of antioxidant defenses

Tissue Cell. 2026 Mar 7:101:103452. doi: 10.1016/j.tice.2026.103452. Online ahead of print.

Authors

Emad H M Hassanein¹, Omnia A M Abd El-Ghafar², Sulaiman M Alnasser³, Reem S Alruhaimi⁴, Hanan S Althagafy⁵, Ahmed M Atwa⁶, Ayman M Mahmoud⁷

Affiliations

¹ Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt.
² Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, Beni-Suef 62521, Egypt.
³ Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 52571, Saudi Arabia.
⁴ Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia.
⁵ Division of Biochemistry, Department of Biological Sciences, Faculty of Science, University of Jeddah, Jeddah 21589, Saudi Arabia.
⁶ Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo 11829, Egypt.
⁷ Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester M1 5GD, UK; Molecular Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt. Electronic address: a.mahmoud@mmu.ac.uk.

PMID: 41819042
DOI: 10.1016/j.tice.2026.103452

Abstract

Cisplatin (CIS) is effective chemotherapeutic agent, but its clinical use is limited by adverse effects, including cardiotoxicity. Safe cardioprotective agents that can be rapidly translated into oncology practice remain an unmet need. This study evaluated whether candesartan (CAN), a clinically approved angiotensin II receptor blocker (ARB), protects against CIS-induced myocardial injury. Male Wistar rats were randomized into control, CAN, CIS, and CAN+CIS groups. CAN (5 mg/kg, oral) was administered for 10 days and CIS (7 mg/kg, i.p.) was injected on day 7. Serum cardiac biomarkers were assessed, oxidative and inflammatory mediators were quantified in cardiac tissue, and histopathology and immunohistochemistry were performed. CIS caused marked myocardial injury, evidenced by elevated cTnI, CK-MB, AST, and LDH, structural degeneration, and necrosis. Oxidative stress was pronounced, with increased lipid peroxidation and MPO activity and depleted antioxidant defenses, accompanied by downregulation of cytoglobin. CAN significantly attenuated biochemical and histological injury, restored redox homeostasis, and preserved cytoglobin expression. CIS also upregulated TLR-4, NF-κB, IRF-3, c-Fos, c-Jun, iNOS, and pro-inflammatory cytokines, whereas CAN markedly suppressed these changes. Molecular docking analysis showed the binding of CAN with cytoglobin, NF-κB p65, IRF-3, and c-Fos/c-Jun complex. In conclusion, CAN confers protection against CIS-induced myocardial damage by mitigating oxidative stress, enhancing antioxidants, and suppressing TLR-4/NF-κB/IRF-3/AP-1 signaling. These findings highlight CAN as a promising adjunct to alleviate CIS-induced cardiotoxicity and preserve cardiovascular health in cancer patients undergoing CIS chemotherapy. However, further investigations and clinical trials are needed to validate these preclinical data.

Keywords: Candesartan; Chemotherapy; Cisplatin; Inflammation; Oxidative stress.