Open Access

ARTICLE

Esculetin Ameliorates Cisplatin-Induced Acute Kidney Injury by Inhibiting Inflammation, Oxidative Stress, and Tubular Cell Death in Mice

Jung-Yeon Kim^#, Min Hui Park^#, Kiryeong Kim, Jaechan Leem^*

Department of Immunology, Daegu Catholic University School of Medicine, Daegu, 42472, Republic of Korea

* Corresponding Author: Jaechan Leem. Email:
# These authors contributed equally to this work

(This article belongs to the Special Issue: Modulation of Inflammation, Oxidative Stress, and Mitochondrial Function: Therapeutic Perspectives Across Diseases)

BIOCELL 2025, 49(11), 2147-2166. https://doi.org/10.32604/biocell.2025.070188

Received 10 July 2025; Accepted 19 September 2025; Issue published 24 November 2025

Abstract

Background: Cisplatin (CDDP) is a cornerstone chemotherapeutic agent for many solid tumors, but its clinical use is severely limited by dose-dependent nephrotoxicity, which results in acute kidney injury (AKI) in a significant proportion of patients. CDDP-induced AKI involves interconnected mechanisms, including inflammation, oxidative stress, and tubular cell death. In this study, we aimed to investigate the renoprotective effects of esculetin (ES), a natural antioxidant coumarin, in a murine model of CDDP-induced AKI. Methods: Male C57BL/6 mice (8–10 weeks) received a single intraperitoneal injection of CDDP (20 mg/kg) with or without ES (40 mg/kg/day, oral gavage). Renal function, histopathology, and molecular markers of inflammation, oxidative stress, mitogen-activated protein kinase (MAPK) activation, endoplasmic reticulum (ER) stress, apoptosis, and ferroptosis were assessed by standard biochemical, histological, and immunoblotting techniques. Results: ES significantly reduced CDDP-induced elevations in serum creatinine and blood urea nitrogen, preserved renal structure, and decreased histological injury scores. Molecular analyses showed that ES suppressed the production of systemic and renal proinflammatory cytokines and inhibited the expression of chemokines and adhesion molecules. ES also suppressed the phosphorylation of extracellular signal-regulated kinase 1/2 and p38 MAPKs, mitigating stress-induced inflammatory and apoptotic signaling. Additionally, ES treatment reduced the expression of unfolded protein response markers, such as C/EBP homologous protein, which is indicative of alleviated ER stress. Oxidative injury was reduced, as evidenced by lower malondialdehyde and 4-hydroxynonenal levels and restored glutathione content. Importantly, ES mitigated ferroptosis, as demonstrated by decreased expression of pro-ferroptotic markers and preservation of anti-ferroptotic mediators, including glutathione peroxidase 4 and solute carrier family 7 member 1. Conclusion: Collectively, our findings provide the first in vivo evidence that ES robustly protects against CDDP-induced AKI by simultaneously targeting oxidative stress, inflammation, MAPK, and ER stress pathways, apoptosis, and ferroptosis. These results highlight ES as a potential candidate for preventing CDDP-induced nephrotoxicity.

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