Natural products in diabetic nephropathy: mechanisms and structure-activity relationships

Diabetic nephropathy (DN), a major microvascular complication of diabetes mellitus, is a leading cause of end-stage renal disease and represents a significant threat to global public health. Currently, clinical management primarily relies on hypoglycemic, antihypertensive, and lipid-lowering agents. Although these therapies can slow the progression of DN, their overall efficacy remains limited due to adverse side effects, poor target specificity, and the multifactorial pathogenesis of the disease. Natural products, predominantly derived from medicinal plants, possess diverse chemical scaffolds and are characterized by multi-target pharmacological actions and broad therapeutic potential. These compounds exert beneficial effects through modulation of key pathological processes, including oxidative stress, inflammatory responses, autophagy, ferroptosis, and renal fibrosis. A literature search was conducted in PubMed and Web of Science for articles published between 2017 and 2025 using keywords including "diabetic nephropathy", "diabetic kidney disease", "natural products", "polyphenols", "phenolic acids", "flavonoids", "flavonols", "flavones", "isoflavones", "iridoids", "saponins", "triterpenoids", "lignans", "stilbenes", "curcuminoids", "quinones", "alkaloids", "phenylethanoid glycosides", "autophagy", "ferroptosis", "NLRP3 inflammasome", "NF-κB", "Nrf2", "PI3K/Akt", "TGF-β/Smad", and "mechanisms". The pharmacological mechanisms of major natural product classes in DN are summarized, covering oxidative stress, inflammation, autophagy, and ferroptosis pathways. In contrast to existing reviews, this study categorizes anti-diabetic nephropathy natural products by chemical scaffold and offers a preliminary structure-activity relationship (SAR) analysis, thereby elucidating the potential link between structural features and pharmacological mechanisms. This provides a new research direction for future target identification and the development of novel anti-diabetic nephropathy agents.