Candesartan preserves aortic structure and function in cisplatin-treated rats by upregulating SIRT1/Nrf2/HO-1 signaling and suppressing oxidative stress, TLR-4/NF-κB signaling, and necroptosis

Background Cisplatin (CIS) is widely used in the treatment of several tumors. However, its use is associated with toxicity that contributes to long-term cardiovascular complications in cancer survivors. This study investigated whether the angiotensin II receptor blocker candesartan (CAN) could protect against CIS-induced aortic injury in rats. Methods Rats received CAN (5 mg/kg, oral) for 10 days, with a single intraperitoneal dose of CIS (7 mg/kg) administered on day 7. Results Histopathological analysis revealed that CIS induced extensive aortic damage, including endothelial disruption, elastic fiber fragmentation, thrombi, and medial calcification, which were significantly alleviated by CAN. CIS-induced oxidative stress was evidenced by elevated lipid peroxidation, myeloperoxidase (MPO) activity, and suppressed antioxidant defenses, while inflammatory activation was marked by upregulation of TLR-4, NF-κB, iNOS, and pro-inflammatory cytokines. CAN treatment reversed these alterations and restored redox balance and anti-inflammatory cytokine IL-10 levels. CAN enhanced SIRT1/Nrf2/HO-1 signaling and suppressed necroptosis-associated proteins (RIP1, RIP3, MLKL, and caspase-8). Molecular docking supported direct interactions between CAN and SIRT1, Keap1, and HO-1. Additionally, CAN corrected the CIS-induced imbalance in the renin-angiotensin system by decreasing angiotensin (Ang) II and increasing Ang-(1–7), and preserved endothelium-dependent vasorelaxation. Conclusion These findings suggest that CAN protects against CIS-induced vascular injury through coordinated suppression of oxidative stress, inflammation, and necroptosis, alongside upregulation of SIRT1/Nrf2/HO-1 signaling and restoration of vascular function. CAN may represent a promising vascular-protective strategy in patients undergoing CIS chemotherapy.