Obesity contributes to the development of metabolic disorders such as type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) through sustained low-grade inflammation and mitochondrial dysfunction. In obesity, hypertrophied adipose tissue release high levels of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, and elevates circulating free fatty acids. These changes promote systemic insulin resistance and ectopic lipid deposition. Mitochondrial dysfunction, including reduced oxidative phosphorylation, excess reactive oxygen species (ROS) production, and mitochondrial DNA damage, further stimulate inflammatory pathways such as the NLRP3 inflammasome, creating a feedback loop that worsens metabolic stress. Ultimately, this interaction disrupts energy balance, weakens insulin signaling, and accelerates β-cell dysfunction and hepatic steatosis. In both T2DM and MASLD, oxidative stress, defective mitochondrial quality control, and dysregulated immunometabolic responses are consistently observed pathophysiological features. Interventions aimed at reducing inflammation and restoring mitochondrial function—including lifestyle modification, mitochondria-targeted therapies, inflammasome regulation, and enhancement of mitochondrial biogenesis or mitophagy—may retard disease progression.

Background/Objectives: 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. Methods: 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. Results: 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. Conclusions: These findings suggest that 4-PBA effectively prevents cisplatin-induced acute kidney injury by suppressing Pdk4.