Dihydroberberine protects against diabetic nephropathy via inhibiting NF-B mediated inflammation and fibrosis

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus characterized by inflammation and fibrosis. Berberine has a favorable therapeutic effect in alleviating DN; however, its extremely low bioavailability limits its clinical use. Dihydroberberine (DHB) is a metabolite of berberine that has higher bioavailability, but its effect in alleviating DN remains unclear. DHB intervention alleviated hyperglycemia, renal dysfunction, and inflammation, while reducing pathological renal damage and fibrosis‑related gene expression in diabetic db/db and high-fat diet (HFD)-induced mice. Next, we investigated the therapeutic potential and molecular mechanisms of DHB in alleviating DN using a combination of network pharmacology, molecular docking, and experimental validation. A public database was used to predict the 3706 targets involved in DN and the 456 targets of DHB. Promoter analysis of DN targets using HOMER motif analysis and Venn analysis revealed nuclear factor kappa B (NF-κB) as the only transcription factor in both groups, suggesting that it could be the main target of DHB in alleviating DN. Molecular docking confirmed the interaction between DHB and NF-κB. In vitro studies revealed that DHB improved the viability of high glucose–/palmitic acid–induced HK-2 cells; reduced NF-κB/p65 and cleaved caspase-3 levels; and suppressed inflammation, fibrosis, and apoptosis markers. In diabetic db/db and HFD-induced mice, DHB treatment also alleviated NF-κB–related inflammation and fibrosis-related gene expression. These findings suggest that DHB ameliorates DN via modulation of the NF-κB pathway, highlighting its potential as a promising therapeutic candidate.