Sodium Phenylbutyrate Attenuates Cisplatin-Induced Acute Kidney Injury Through Inhibition of Pyruvate Dehydrogenase Kinase 4

<b>Background/Objectives:</b> Cisplatin nephrotoxicity is a significant clinical issue, and currently, no approved drug exists to prevent cisplatin-induced acute kidney injury (AKI). This study investigated whether sodium phenylbutyrate (4-PBA), a chemical chaperone, can prevent cisplatin-induced AKI. <b>Methods:</b> Six consecutive days of intraperitoneal injections of 4-PBA were administered in a murine model before and after the cisplatin challenge. This study evaluated tubular injury, serum blood urea nitrogen (BUN) and creatinine levels, and inflammatory markers such as tumor necrosis factor-alpha (TNF-α) and intercellular adhesion molecule 1 (ICAM-1). Additionally, apoptosis, mitochondrial membrane potential, oxygen consumption ratio, and reactive oxygen species (ROS) were assessed in renal tubular cells. The expression levels of pyruvate dehydrogenase kinase 4 (Pdk4) were also analyzed. <b>Results:</b> 4-PBA prevented tubular injury and normalized serum BUN and creatinine levels. Inflammatory markers TNF-α and ICAM-1 were suppressed. In renal tubular cells, 4-PBA reduced apoptosis, restored mitochondrial membrane potential and oxygen consumption ratio, and reduced ROS production. Mechanistically, 4-PBA suppressed the expression of Pdk4, which is known to be induced during cisplatin-induced renal injury. The protective effect of 4-PBA was abolished in Pdk4-overexpressing renal tubular cells, indicating that the efficacy of 4-PBA partially depends on the suppression of Pdk4 expression. In cancer cells, 4-PBA did not interfere with the anti-cancer efficacy of cisplatin. <b>Conclusions:</b> These findings suggest that 4-PBA effectively prevents cisplatin-induced acute kidney injury by suppressing Pdk4.