Natural product therapy in diabetic kidney disease: emerging multiomics-mediated signalling pathway and molecular target.

Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes, with high mortality and morbidity, and is a major cause of progression to end-stage renal disease (ESRD). Although inhibitors or blockers of renin-angiotensin system blockers have a beneficial effect on the treatment of DKD, most patients progress to ESRD and ultimately require renal replacement therapies. Extensive studies have suggested that natural products, as a mainly new drug source, has been demonstrated to be an important therapy for the prevention and treatment of DKD. Based on genomics, transcriptomics, proteomics and metabolomics technologies, the dysregulation of targeting multiomics-associated gut microbiota, non-coding RNAs, altered proteome and endogenous metabolites has recognized as a promising therapy for DKD. This review summarizes natural products, including traditional Chinese medicine formulas (Qitu Qushi formula, Jin Gui Ren Qi Pill and Huangkui capsules), single herbal extracts (Salvia miltiorrhiza, Korean red ginseng, Abelmoschus manihot flowers) and natural compounds (magnesium lithospermate B, thonningianin A germacrone, triptolide, hesperetin, astragaloside IV, icariin and kaempferol) as well as natural polysaccharides, protect against DKD by regulating novel multiomics-associated molecular mechanisms, including gut microbiota dysbiosis, aberrant non-coding RNAs transcription, and disorder of endogenous metabolites and associated with downstream diverse signals, such as IκB/NF-κB, JAK/STAT, MAPK and NLRP3-mediated inflammation pathways, AGEs/RAGE and Keap1/Nrf2-mediated oxidative stress pathways, PI3K/AKT/mTOR, AMPK and endoplasmic reticulum stress-mediated energy/autophagy pathways and TGF-β/Smad and Wnt/β-catenin-mediated fibrosis pathways. Therefore, the underlying molecular mechanism by which natural products ameliorate DKD by reshaping GM dysbiosis, restoring aberrant expression of ncRNAs and regulating metabolite disorder will provide new therapeutic targets for treatment of DKD of natural products. These findings expand our understanding of therapeutic effects of natural products on DKD and provide valuable information for clinical application of natural products. This review presents a concept-driven therapeutic strategy for DKD treatment and management.