Mechanisms of hesperetin in alleviating diabetic nephropathy: Network pharmacology, molecular docking, and experimental validation

Background: Diabetic nephropathy (DN) accounts for approximately 50% of chronic kidney disease cases. This study explored the potential regulatory mechanisms of hesperetin in DN.

Methods: High glucose (HG)-treated HK-2 cells and streptozotocin (STZ)-induced diabetic mice were used as DN models. Impacts on cells were assessed by detecting viability, Apoptosis, inflammatory cytokine release, and malondialdehyde (MDA), ferrous iron (Fe²⁺), and Reactive Oxygen Species (ROS) levels. Network pharmacology and molecular docking were utilized to verify the target of hesperetin in DN.

Results: Hesperetin increased cell viability and decreased Apoptosis, the release of inflammatory cytokines, and the levels of MDA, Fe²⁺, and ROS in HG-induced HK-2 cells. Hesperetin demonstrated high-affinity binding to insulin-like growth factor 1 receptor (IGF1R). IGF1R was highly expressed in HG-treated HK-2 cells, and its silencing exerted protective effects in HK-2 cells under the HG context. IGF1R overexpression reversed the protective effects of hesperetin in HG-treated HK-2 cells. Hesperetin ameliorated DN progression partly via suppressing IGF1R expression.

Conclusions: Hesperetin alleviates DN progression by increasing cell viability and decreasing Apoptosis, inflammatory cytokine release, and Ferroptosis in HK-2 cells partially via modulating IGF1R expression.