Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2023.062
Synergistic Renoprotective Effect of Melatonin and Zileuton by Inhibition of Ferroptosis via the AKT/mTOR/NRF2 Signaling in Kidney Injury and Fibrosis
Kyung Hee Jung1,†, Sang Eun Kim1,†, Han Gyeol Go1, Yun Ji Lee1, Min Seok Park1, Soyeon Ko1, Beom Seok Han1, Young-Chan Yoon1, Ye Jin Cho1, Pureunchowon Lee1, Sang-Ho Lee2, Kipyo Kim3,* and Soon-Sun Hong1,*
1Department of Medicine, College of Medicine, and Program in Biomedical Science & Engineering, Inha University, Incheon 22332, 2Division of Nephrology, Department of Internal Medicine, College of Medicine, Kyung Hee University, Seoul 02453, 3Divison of Nephrology and Hypertension, Department of Internal Medicine, Inha University Hospital, Inha University College of Medicine, Incheon 22332, Republic of Korea
*E-mail: hongs@inha.ac.kr (Hong SS), kpkidney@inha.ac.kr (Kim K)
Tel: +82-32-890-3683 (Hong SS), +82-32-890-3246 (Kim K)
Fax: +82-32-890-2462 (Hong SS), +82-32-890-2462 (Kim K)
†The first two authors contributed equally to this work.
Received: March 23, 2023; Revised: April 7, 2023; Accepted: April 17, 2023; Published online: May 15, 2023.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
According to recent evidence, ferroptosis is a major cell death mechanism in the pathogenesis of kidney injury and fibrosis. Despite the renoprotective effects of classical ferroptosis inhibitors, therapeutic approaches targeting kidney ferroptosis remain limited. In this study, we assessed the renoprotective effects of melatonin and zileuton as a novel therapeutic strategy against ferroptosis-mediated kidney injury and fibrosis. First, we identified RSL3-induced ferroptosis in renal tubular epithelial HK-2 and HKC-8 cells. Lipid peroxidation and cell death induced by RSL3 were synergistically mitigated by the combination of melatonin and zileuton. Combination treatment significantly downregulated the expression of ferroptosis-associated proteins, 4-HNE and HO-1, and upregulated the expression of GPX4. The expression levels of p-AKT and p-mTOR also increased, in addition to that of NRF2 in renal tubular epithelial cells. When melatonin (20 mg/kg) and zileuton (20 mg/kg) were administered to a unilateral ureteral obstruction (UUO) mouse model, the combination significantly reduced tubular injury and fibrosis by decreasing the expression of profibrotic markers, such as α-SMA and fibronectin. More importantly, the combination ameliorated the increase in 4-HNE levels and decreased GPX4 expression in UUO mice. Overall, the combination of melatonin and zileuton was found to effectively ameliorate ferroptosis-related kidney injury by upregulating the AKT/mTOR/ NRF2 signaling pathway, suggesting a promising therapeutic strategy for protection against ferroptosis-mediated kidney injury and fibrosis.
Keywords: Ferroptosis, RSL3, Kidney injury, Fibrosis, GPX4

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