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<p>Radiotherapy is crucial in curative oncology, but normal tissue injuries, such as the kidney, restrict its usage. While rosuvastatin (ROSU) is experimentally&#xa0;known to mitigate renal damage, its potential role in protecting against radiation-induced nephrotoxicity has never been investigated. Accordingly, the current study explored the ROSU’s protective impact against radiation-induced nephropathy, with a particular focus on mitophagy regulation. Animals were exposed to 8 Gray (Gy) of whole-body gamma irradiation, either acute or fractionated (2&#xa0;Gy × 4), and received ROSU (10&#xa0;mg/kg, i.p.) pre- and post-radiation. Kidney injury was assessed by estimating kidney functions, oxidative stress parameters, and histopathological alterations. To elucidate the mechanism of ROSU, the gene and protein expression of sirtuin&#xa0;1 (SIRT1) and forkhead box class O (FOXO3a) were estimated, alongside mitophagy and apoptotic biomarkers. Radiation exposure induced cellular necrosis and apoptosis, impaired renal function, and oxidative imbalance. ROSU treatment&#xa0;markedly ameliorated these alterations, demonstrating potent antioxidant activity, as evidenced by reduced malondialdehyde (MDA) level&#xa0;and elevated reduced glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD) levels. Mechanistically, ROSU activated SIRT1 and promoted FOXO3a deacetylation, thereby restoring radiation-impaired mitophagy, as indicated by increased expression of PTEN-induced putative kinase protein 1 (PINK1), Parkinson protein 2 E3 ubiquitin protein ligase (Parkin), and autophagy-related gene 5 (ATG5). This was accompanied by the suppression of intrinsic apoptosis triggered by radiation, as shown by decreased cleaved caspase-3 expression. This study repurposes ROSU in modulating radiation-induced nephropathy, revealing its novel role in redirecting cell fate from apoptosis toward mitophagy through SIRT1/FOXO3a activation.</p>

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Role of mitophagy in acute and fractionated gamma radiation–induced nephropathy in rats: insight into molecular biology and repurposing of rosuvastatin

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月29日

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  • Noha A. Fadel,
  • Dina M. Lotfy,
  • Asmaa A. Gomaa,
  • Abeer Bishr

摘要

Radiotherapy is crucial in curative oncology, but normal tissue injuries, such as the kidney, restrict its usage. While rosuvastatin (ROSU) is experimentally known to mitigate renal damage, its potential role in protecting against radiation-induced nephrotoxicity has never been investigated. Accordingly, the current study explored the ROSU’s protective impact against radiation-induced nephropathy, with a particular focus on mitophagy regulation. Animals were exposed to 8 Gray (Gy) of whole-body gamma irradiation, either acute or fractionated (2 Gy × 4), and received ROSU (10 mg/kg, i.p.) pre- and post-radiation. Kidney injury was assessed by estimating kidney functions, oxidative stress parameters, and histopathological alterations. To elucidate the mechanism of ROSU, the gene and protein expression of sirtuin 1 (SIRT1) and forkhead box class O (FOXO3a) were estimated, alongside mitophagy and apoptotic biomarkers. Radiation exposure induced cellular necrosis and apoptosis, impaired renal function, and oxidative imbalance. ROSU treatment markedly ameliorated these alterations, demonstrating potent antioxidant activity, as evidenced by reduced malondialdehyde (MDA) level and elevated reduced glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD) levels. Mechanistically, ROSU activated SIRT1 and promoted FOXO3a deacetylation, thereby restoring radiation-impaired mitophagy, as indicated by increased expression of PTEN-induced putative kinase protein 1 (PINK1), Parkinson protein 2 E3 ubiquitin protein ligase (Parkin), and autophagy-related gene 5 (ATG5). This was accompanied by the suppression of intrinsic apoptosis triggered by radiation, as shown by decreased cleaved caspase-3 expression. This study repurposes ROSU in modulating radiation-induced nephropathy, revealing its novel role in redirecting cell fate from apoptosis toward mitophagy through SIRT1/FOXO3a activation.