Diacerein Ameliorates Gentamicin‐Induced Nephrotoxicity via Regulating PI3k/AKT‐Mediated Nrf‐2 and NF‐κB Pathways: Forge the Mechanistic Insight

Nephrotoxicity is one of the most significant therapeutic limitations of gentamicin (GM) antibiotics, strongly linked to oxidative stress and apoptotic pathways. In this study, diacerein (DIA), an antiarthritic agent with potent antioxidant and anti-inflammatory properties, was investigated for its renoprotective potential and underlying mechanisms in GM-induced nephrotoxicity. Rats received GM (100 mg/kg, i.p.) alone or with DIA (25 or 50 mg/kg) for 10 days. Kidney tissues were assessed for histological damage, oxidative stress, apoptotic and inflammatory markers, and key signaling pathway activities. Structural equation modeling (SEM) was performed to explore mechanistic interactions and biomarker predictive. In a dose-dependent manner, DIA mitigated renal histopathological disturbance and attenuated the imbalanced oxidative status in GM-challenged rats by reducing renal MDA levels, as well as stimulating catalase and SOD activities and Nrf2 protein expression. DIA also attenuated GM-induced inflammation and apoptosis by suppressing NF-κB and cleaved caspase-3 expression. DIA restoration of phosphorylated PI3K and AKT protein expression, suggesting activation of the PI3K/AKT/Nrf2/NF-κB signaling pathway. Principal component analysis (PCA) extracted one dominant component (PC1) as the antioxidant-oxidative stress axis, explaining over 90% of the total variance. SEM further supported a mechanistic framework wherein PI3K strongly influenced AKT, which upregulated Nrf2 (β = 0.66, p < 0.001) and, in turn, enhanced CAT and SOD (β = 0.86 and 0.83, p < 0.001). The model reinforces AKT-Nrf2-CAT axis as a critical pathway modulating caspase-dependent apoptosis. DIA exhibits renal protection in GM-induced nephrotoxicity mainly through modulating PI3K/AKT/Nrf2 signaling pathways. PCA and SEM analyses provide novel mechanistic and diagnostic insights that enhance the translational potential of the findings.