Chrysin attenuates tramadol-driven renal dysfunction via regulation of RNA networks, antioxidant pathways, and ketogenic metabolism

This study aimed to evaluate the nephrotoxic effects of tramadol (TR) on renal function and the possible protective role of chrysin (CH) based on multiple biochemical, molecular, and metabolic parameters. The administration of TR resulted in substantial elevations in serum creatinine and BUN levels, concurrently increasing renal damage biomarkers including KIM-1, NGAL, FABP, IL-18, MCP-1, and YKL-40. Furthermore, elevated mRNA levels of Cst3, Timp2, Igfbp7, Hgf, IL-9, and Dkk3 were noted, along with a significant increase in inflammation-related proteins IL-1β, IL-3, IL-4, IL-5, IL-6, and IL-21. TR interrupted LINC01187 and additional regulatory RNA networks, reduced the concentrations of β-hydroxybutyrate, NAD+, and acetyl-CoA, essential for ketogenesis, and inhibited HMGCS2 expression. Furthermore, reduced levels of Nrf2, PPARγ, XCT, GPX4, and FPN proteins elevated oxidative stress, diminished SOD, CAT, and GPX levels, and heightened MDA concentrations. The CH administration resulted in partial or substantial enhancement in all these parameters, mitigating the molecular, metabolic, and functional decline induced by TR. PCA analysis indicated that CH aligned the biomarker profile more closely with normal physiological levels. These findings indicate that CH may serve as a potential nephroprotective agent in TR-induced renal injury.