Forest-cultivated Epimedium koreanum Nakai mitigates organotin-induced renal injury and the exacerbation of diabetic nephropathy via the SIRT1/NRF2/PPARγ signaling pathways.

BACKGROUND

Organotin compounds, such as tributyltin (TBT) and triphenyltin (TPT), are persistent environmental pollutants; however, their role in exacerbating chronic kidney diseases remains poorly understood. This study identifies how organotins exploit metabolic vulnerabilities in diabetic nephropathy (DN) and demonstrates the superior protective efficacy of Epimedium koreanum Nakai cultivated in forest (EKF) over conventional varieties.

METHODS

We integrated in silico modeling and network toxicology with in vitro validation using human renal proximal tubular epithelial cells. Cells derived from normal and diabetic conditions were exposed to organotins. Untargeted metabolomics identified bioactive constituents in EKF. Mechanistic validation was conducted using siRNA-mediated SIRT1 ablation and pharmacological inhibition (Ex-527) to define the regulatory role of the SIRT1/NRF2/PPARγ axis.

RESULTS

Network toxicology identified the SIRT1/NRF2/PPARγ axis as a central node of organotin-induced renal damage. In vitro, a diabetic environment significantly exacerbated organotin-induced cytotoxicity (p < 0.05), characterized by a surge in reactive oxygen species and aberrant induction of the obesogenic marker PPARγ. EKF provided superior protection against redox collapse and lipotoxicity compared to open-field varieties. Untargeted metabolomics identified Acetyl-l-carnitine (ALCAR) as a key bioactive constituent in EKF that restores SIRT1 expression. We demonstrate that EKF requires SIRT1 catalytic activity to re-activate the NRF2/HO-1/GSTP1 antioxidant defense while restricting pathological PPARγ-mediated lipid peroxidation. Notably, silencing or inhibiting SIRT1 significantly abrogated the protective effects of EKF on downstream NRF2 and PPARγ pathways.

CONCLUSION

These findings establish the SIRT1/NRF2/PPARγ axis as a mandatory mediator of renal resilience against organotin-exacerbated diabetic nephropathy. EKF mitigates injury by recruiting the SIRT1 metabolic sensor to restore renal equilibrium. EKF supplementation represents a strategic intervention to decouple environmental pollutant exposure from metabolic disease progression in high-risk populations.