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

ABSTRACT 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 (Fe 2+ ), 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, Fe 2+ , 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.