Huangkui capsule mitigates diabetic nephropathy via epigenetic therapy effects

Background Huangkui capsule (HKC), a Chinese herbal medicine derived from Abelmoschus manihot (L.) ethanol extract, has clinical efficacy against diabetic nephropathy (DN). Our research group has actively engaged in exploring the efficacy of HKC in treating DN. The underlying pharmacological mechanisms have progressively become clearer but its epigenetic mechanisms remain unclear. Objective To elucidate HKC’s epigenetic role in the treatment of DN. Methods Db/db mice (a type 2 diabetes/DN model) were orally administered HKC or vehicle for 4 weeks. Kidney tissues underwent whole-genome bisulfite sequencing and transcriptome profiling to assess DNA methylation and gene expression patterns. Results HKC significantly reduced urinary albumin/creatinine ratios, indicating renal protection. Comparative methylation analysis revealed HKC regulated the distribution of 5 mC by modulating Tet2 expression, thereby influencing abnormal methylation patterns in DN. Integrative analysis identified 12 DN-associated genes with reversed methylation and expression post-HKC treatment, including Cdk8, Pde4d, Pisd-ps3 , and Zc3h7a , which showed high susceptibility to DN progression and HKC intervention. Functional annotation linked these genes to immune regulation, synaptic signaling, and Notch pathways. Conclusion This study provides the first evidence that HKC ameliorates DN through epigenetic therapy effects, specifically by restoring DNA methylation and transcriptional activity of renal target genes. Further biological experiments to validate these findings are necessary.