Amelioration of nephrotoxicity by targeting ferroptosis: role of NCOA4, IREB2, and SLC7a11 signaling

• Published in: Brazilian journal of medical and biological research Vol. 57; p. e13116
• Main Authors: Sharawy, N, Aboulhoda, B E, Khalifa, M M, Morcos, G N, Morsy, S A A G, Alghamdi, M A, Khalifa, I M, Abd Algaleel, W A
• Format: Journal Article
• Language: English
• Published: Brazil Associação Brasileira de Divulgação Científica 01.01.2024
• Subjects: Amino Acid Transport System y+ - metabolism; Animals; Antineoplastic Agents; BIOLOGY; Cisplatin; Cisplatin - toxicity; Deferiprone; Deferiprone - pharmacology; Ferritinophagy; Ferritins - metabolism; Ferroptosis; Ferroptosis - drug effects; Immunohistochemistry; Iron; Iron - metabolism; Kidney; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney Diseases - chemically induced; Kidney Diseases - metabolism; Lipid Peroxidation - drug effects; Male; MEDICINE, RESEARCH & EXPERIMENTAL; Nuclear Receptor Coactivators - metabolism; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Ferroptosis; Ferritinophagy; Iron; Deferiprone; Kidney; Cisplatin
• ISSN: 0100-879X; 1414-431X; 1414-431X
• DOI: 10.1590/1414-431X2024e13116

Nephrotoxicity is a common complication that limits the clinical utility of cisplatin. Ferroptosis is an iron-dependent necrotic cell death program that is mediated by phospholipid peroxidation. The molecular mechanisms that disrupt iron homeostasis and lead to ferroptosis are yet to be elucidated. In this study, we aimed to investigate the involvement of nuclear receptor coactivator 4 (NCOA4), a selective cargo receptor that mediates ferroptosis and autophagic degradation of ferritin in nephrotoxicity. Adult male Sprague-Dawley rats were randomly-assigned to four groups: control group, cisplatin (Cis)-treated group, deferiprone (DEF)-treated group, and Cis+DEF co-treated group. Serum, urine, and kidneys were isolated to perform biochemical, morphometric, and immunohistochemical analysis. Iron accumulation was found to predispose to ferroptotic damage of the renal tubular cells. Treatment with deferiprone highlights the role of ferroptosis in nephrotoxicity. Upregulation of NCOA4 in parallel with low ferritin level in renal tissue seems to participate in iron-induced ferroptosis. This study indicated that ferroptosis may participate in cisplatin-induced tubular cell death and nephrotoxicity through iron-mediated lipid peroxidation. Iron dyshomeostasis could be attributed to NCOA4-mediated ferritin degradation.