Natural products modulate renal metabolic reprogramming in diabetic kidney disease

Natural products against renal fibrosis: molecular mechanisms, safety concerns, and translational perspectives

Abstract Renal fibrosis represents a shared pathological endpoint that drives the progression of chronic kidney disease (CKD) toward end-stage kidney disease (ESKD). Although current therapies can delay CKD progression, they have limited capacity to reverse established fibrotic remodeling, underscoring the need for mechanism-oriented anti-fibrotic interventions. Plant-derived preparations have long attracted attention because of their multi-component, multi-target, and multi-pathway pharmacological profiles. More recently, advances in separation, purification, and pharmacological evaluation have redirected research interest from crude extracts toward defined bioactive natural products. A growing body of evidence suggests that flavonoids, alkaloids, terpenoids, glycosides, polyphenols, quinones, and other natural products may exert anti-fibrotic effects by targeting key pathological processes, including inflammation, oxidative stress, mitochondrial dysfunction, metabolic reprogramming, autophagy dysregulation, epigenetic regulation, and regulated cell death. This review summarizes recent advances in the use of natural products for the treatment of renal fibrosis, with a particular focus on their underlying molecular mechanisms, current status of clinical translation, and the challenges that remain.

Advances in the Treatment of Diabetic Kidney Disease With Traditional Chinese Medicine.

Diabetic kidney disease (DKD) persists as the predominant etiology of end-stage renal disease globally. Despite advances in conventional pharmacotherapies, which primarily target single pathogenic pathways, a considerable residual risk of renal function decline and end-stage renal disease progression remains unresolved, highlighting the need for alternative therapeutic paradigms. This review involves dissecting and integrating mechanistic insights derived from preclinical investigations, including in vitro cellular models, in vivo animal models of DKD, and molecular biology-based analyses. It uses Tangshen formula, a classic traditional Chinese medicine (TCM) for DKD, to detail TCM's protective mechanisms and concisely summarizes the DKD-related preclinical progress of other TCMs over 5 years. Unlike monotarget strategies, TCM interventions exert synergistic effects across multiple organ systems: they reshape the renal microenvironment by mitigating oxidative stress and extracellular matrix accumulation, reprogram hepatic glucose and lipid metabolism to alleviate insulin resistance, and fortify the intestinal mucosal barrier to prevent endotoxemia-induced systemic inflammation. At the microscopic and molecular levels, these TCM-derived agents orchestrate coordinated crosstalk among key pathogenic cascades, including chronic inflammation, renal fibrosis, gut microbiota dysbiosis, metabolic flux dysregulation, microcirculatory impairment, and hypoxic injury. By targeting these interconnected pathways simultaneously, TCM facilitates the restoration of systemic homeostasis, thereby addressing the complex, multifactorial pathogenesis of DKD more comprehensively than pathway-specific interventions.

Metabolic reprogramming in diabetic complications: mechanisms, pathologies, and molecular evidence from multi-organ studies

Metabolic reprogramming is a critical link between systemic metabolic dysregulation and organ-specific, persistent injury in diabetic complications. Previous reviews have largely focused on individual organs or isolated metabolic pathways, leaving unresolved how common diabetic metabolic reprogramming is translated into divergent tissue injury across different organs and cell types. Addressing this gap is important because it connects fragmented pathway-level evidence with tissue-specific disease mechanisms and may help prioritize more precise therapeutic strategies for diabetic complications. This review summarizes alterations in glucose, lipid, and amino acid metabolism, mitochondrial function, immunometabolism, and epigenetic regulation in diabetic kidney disease, diabetic retinopathy, diabetic foot ulcers, diabetic peripheral neuropathy, and diabetic cardiovascular complications. Current evidence indicates that hypoxia-inducible factor 1α (HIF-1α)-driven glycolysis, ferroptosis-associated oxidative stress, mitochondrial dysfunction, dysregulated nutrient sensing, and inflammatory metabolic remodeling are shared across multiple diabetic complications. However, their downstream consequences are highly dependent on tissue-specific microenvironments and resident-cell composition. For example, HIF-1α-related glycolytic remodeling promotes macrophage-driven inflammation and fibrosis in diabetic kidney disease but contributes to Müller-cell-derived VEGF/ANGPTL4 expression and pathological angiogenesis in diabetic retinopathy. Similarly, ferroptosis-associated lipid injury causes endothelial repair failure in diabetic foot ulcers but cardiomyocyte injury and cardiac remodeling in diabetic cardiovascular complications. These examples suggest that local oxygen status, metabolic demand, immune-cell composition, intercellular metabolic crosstalk, and tissue repair capacity reshape shared metabolic programs into organ-specific pathological outcomes, including filtration-barrier injury, vascular leakage, impaired wound healing, neuropathic injury, and cardiac dysfunction. Moreover, hyperglycemia-induced oxidative stress, inflammatory metabolic remodeling, and epigenetic alterations may persist after glycemic improvement and contribute to metabolic memory. By integrating evidence across organs and cell types, this review provides a new perspective for understanding why shared metabolic reprogramming in diabetes produces tissue-specific pathological outcomes. Therapeutic strategies should therefore combine glycemic control with interventions targeting both shared metabolic pathways and organ- or cell-specific pathogenic mechanisms.

Epigenetic regulation of tubular epithelial cell dysfunction in diabetic kidney disease.

Metabolic Reprogramming and Immunometabolic Dysregulation in Diabetic Kidney Disease: From Pathogenesis to Precision Multi-target Therapies

Diabetic kidney disease, the leading cause of end-stage kidney disease worldwide, involves complex interactions beyond classical hemodynamic and oxidative stress pathways. Recent advances emphasize metabolic reprogramming in renal cells—characterized by mitochondrial dysfunction, impaired fatty acid oxidation, lipotoxicity, and glycolytic shifts—as upstream drivers of cellular injury and fibrosis. Single-cell RNA sequencing reveals profound immunometabolic heterogeneity, including dynamic macrophage subpopulations (e.g., proinflammatory early states transitioning to TREM2hi/MRC1hi lipid-associated phenotypes) and T helper 17/regulatory T imbalance, which amplify inflammation via bidirectional crosstalk with podocytes, tubular cells, and mesangial cells. Interorgan axes, particularly gut dysbiosis and uremic toxin accumulation, further perpetuate immune dysregulation. This review integrates these insights to propose precision strategies targeting mitochondrial homeostasis, ferroptosis inhibition, glycolytic blockade in immune cells, and multimodal therapies (e.g., combination strategies integrating sodium–glucose cotransporter 2 inhibitors with immunometabolic modulators). Multi-omics integration and spatial transcriptomics hold promise for individualized and mechanism-guided interventions to halt diabetic kidney disease progression.

Bidirectional regulation between mitochondrial metabolic reprogramming and epigenetic modifications in renal tubular epithelial cell injury of diabetic kidney disease

Background Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) worldwide. Renal tubular epithelial cell (RTEC) injury is a core driver of DKD initiation and progression. Mitochondrial metabolic reprogramming and epigenetic modification are two core events in DKD pathogenesis, and their bidirectional crosstalk has become a frontier and hot research topic in the pathogenesis of DKD. At present, the specific molecular mechanisms of their bidirectional regulation remain incompletely elucidated. Methods This narrative review collected literatures from PubMed, Web of Science and Embase up to March 2026. English original articles and reviews were included, whereas case reports, letters and non-English publications were excluded. We summarized the latest advances concerning the interaction between mitochondrial metabolic reprogramming and epigenetic modification in RTEC injury of DKD, focusing on their bidirectional molecular regulation. Results Key mitochondrial metabolic intermediates (acetyl-CoA, α-ketoglutarate (α-KG), nicotinamide adenine dinucleotide (NAD+)) act as substrates or cofactors of epigenetic enzymes to regulate DNA methylation, histone modifications, and noncoding RNA expression in RTECs. Epigenetic modifications in turn remodel mitochondrial biogenesis, fatty acid oxidation, and oxidative phosphorylation by regulating the expression of metabolism-related genes. Conclusion This narrative review elaborates the closed-loop crosstalk between mitochondrial metabolism and epigenetics in tubular injury, highlights the therapeutic prospect of targeting this bidirectional regulatory axis, and provides novel theoretical evidence for revealing DKD pathogenesis and developing targeted intervention regimens.