Multidimensional mechanisms of natural products in modulating metabolic dysfunction-associated kidney disease: recent advances and future perspectives.

Metabolic dysfunction-associated kidney disease (MDAKD), encompassing diabetic kidney disease (DKD), obesity-related glomerulopathy (ORG), and hyperuricemic nephropathy (HN), has emerged as a major global health challenge alongside the increasing prevalence of metabolic syndrome. The development and progression of MDAKD are driven by a complex pathogenic network involving metabolic dysregulation, gut microbiota imbalance, oxidative stress, mitochondrial dysfunction, chronic inflammation, and renal fibrosis. Although previous reviews have focused on individual pathogenic mechanisms or specific disease subtypes, comprehensive syntheses integrating distinct MDAKD subtypes within a unified framework while systematically elucidating the multidimensional regulatory mechanisms of natural products remain limited. Natural products have attracted growing attention owing to their multi-component and multi-target pharmacological properties. Increasing evidence suggests that their therapeutic potential extends beyond the modulation of individual pathogenic pathways, encompassing the coordinated regulation of multiple interconnected pathological networks. Diverse bioactive constituents, including polysaccharides, flavonoids, phenolic acids, triterpenes, alkaloids, and saponins, have demonstrated considerable renoprotective effects. Compared with conventional single-pathway interventions, the multi-target regulatory characteristics of natural products, together with their generally favorable safety and tolerability profiles, make them particularly suited to the multifactorial nature of MDAKD. This review systematically summarizes the key pathogenic mechanisms underlying MDAKD and comprehensively discusses recent advances in natural product-based interventions from both mechanistic and pharmacological perspectives. Current evidence indicates that natural products exert renoprotective effects through the coordinated modulation of multiple interconnected pathological processes, thereby establishing a multidimensional regulatory pattern that closely aligns with the complex pathophysiology of MDAKD. Despite challenges related to limited bioavailability, incompletely characterized pharmacokinetic properties, insufficient safety evaluation, and the lack of high-quality clinical evidence, natural products remain promising candidates for the integrated management of MDAKD. Accordingly, this review proposes a multidimensional regulatory framework for natural product-mediated interventions in MDAKD, providing a theoretical basis for future mechanistic studies, drug development, and clinical research.