β-Hydroxybutyrate Protects Against Cisplatin-Induced Renal Damage via Regulating Ferroptosis

Cisplatin is a particularly potent antineoplastic drug. However, its usefulness is restricted due to the induction of nephrotoxicity. More recent research has indicated that beta-hydroxybutyrate (beta-HB) protects against acute or chronic organ damage as an efficient healing agent. Nonetheless, the therapeutic mechanisms of beta-HB in acute kidney damage caused by chemotherapeutic drugs remain unclear. Our study developed a model of cisplatin-induced acute kidney injury (AKI), which involved the administration of a ketogenic diet or beta-HB. We analyzed blood urea nitrogen (BUN) and creatinine (Cr) levels in serum, and used western blotting and immunohistochemical staining to assess ferroptosis and the calcium/calmodulin-dependent kinase kinase 2 (Camkk2)/AMPK pathway. The mitochondrial morphology and function were examined. Additionally, we conducted in vivo and in vitro experiments using selective Camkk2 inhibitor or activator to investigate the protective mechanism of beta-HB on cisplatin-induced AKI. Exogenous or endogenous beta-HB effectively alleviated cisplatin-induced abnormally elevated levels of BUN and Cr and renal tubular necrosis in vivo. Additionally, beta-HB reduced ferroptosis biomarkers and increased the levels of anti-ferroptosis biomarkers in the kidney. beta-HB also improved mitochondrial morphology and function. Moreover, beta-HB significantly attenuated cisplatin-induced cell ferroptosis and damage in vitro. Furthermore, western blotting and immunohistochemical staining indicated that beta-HB may prevent kidney injury by regulating the Camkk2-AMPK pathway. The use of the Camkk2 inhibitor or activator verified the involvement of Camkk2 in the renal protection by beta-HB. This study provided evidence of the protective effects of beta-HB against cisplatin-induced nephrotoxicity and identified inhibited ferroptosis and Camkk2 as potential molecular mechanisms. Cisplatin induces disruptions in mitochondrial energy metabolism and lipid peroxidation. Both endogenous and exogenous beta-hydroxybutyrate can protected against cisplatin-induced renal damage by repairing mitochondrial energy homeostasis and preventing ferroptosis, and this protective effect might be attributed to Camkk2 regulation. beta-HB protects against cisplatin-induced renal damage both in vivo and in vitro.Moreover, beta-HB is effective in attenuating cisplatin-induced lipid peroxidation and ferroptosis.The regulation of energy metabolism, as well as the treatment involving beta-HB, is associated with Camkk2.