Remodeling lipid and mitochondrial homeostasis: a novel mechanism by which polydatin attenuates renal tubular senescence in chronic kidney disease.

Disruption of cellular iron homeostasis by SRPX2-IRP1 interaction aggravates renal fibrosis in chronic kidney disease.

Redox-Mediated Mitochondrial Dysfunction as a Common Pathogenic Axis in Acute Kidney Injury and Chronic Kidney Disease

Overall, redox-mediated mitochondrial injury represents a shared pathogenic axis and a potential therapeutic target across kidney diseases, and emerging biomarkers and therapeutic strategies targeting oxidative stress and mitochondrial dysfunction are discussed.

Systems-level proteomic reprogramming reveals mitochondrial restoration and inhibition of Rho GTPase-mediated cytoskeletal and inflammatory signaling in CKD

Chronic kidney disease (CKD) is a progressive disorder characterized by metabolic dysfunction, mitochondrial impairment, oxidative stress, and chronic inflammation, ultimately leading to irreversible renal damage. Despite advances in understanding CKD pathophysiology, effective therapies targeting these interconnected molecular processes remain limited. In this study, we performed a comprehensive data-independent acquisition (DIA)-based proteomic analysis to investigate the molecular alterations associated with CKD and to evaluate the therapeutic impact of DVA treatment. Using a CKD model with three treatment conditions (DVA, KY, and DVA+KY) alongside disease and healthy controls, we quantified global proteomic changes and applied statistical filtering (fold change ≥2, p ≤0.05) followed by K-means clustering (k=10). Distinct protein clusters revealed bidirectional modulation upon DVA treatment. Notably, Cluster 1 comprised proteins downregulated in CKD but significantly restored following DVA administration, while Cluster 2 included proteins elevated in CKD that were suppressed by DVA. Pathway enrichment and network analyses demonstrated that Cluster 1 proteins were predominantly associated with mitochondrial function, oxidative phosphorylation, and metabolic processes, whereas Cluster 2 proteins were enriched in immune signaling, oxidative stress, cytoskeletal remodeling, and proteostasis pathways. At the molecular level, DVA treatment restored key mitochondrial and metabolic regulators, including components of the electron transport chain (e.g., COX5A, NDUFS5, SDHB) and redox homeostasis proteins, indicating recovery of cellular bioenergetics. Concurrently, DVA suppressed inflammatory mediators (STAT2, IFI47, GBP2), oxidative stress-related proteins (CYBB, PRDX5), and cytoskeletal regulators linked to renal injury (ARHGEF12, FMNL2). Network and Reactome analyses further confirmed coordinated modulation of interconnected biological systems rather than isolated protein changes. Collectively, our findings demonstrate that DVA exerts a dual therapeutic effect by restoring essential mitochondrial and metabolic pathways while simultaneously suppressing inflammation, oxidative stress, and cytoskeletal dysregulation in CKD. This systems-level proteomic reprogramming highlights DVA as a promising candidate for CKD intervention and provides mechanistic insights into disease progression and therapeutic targeting.

Oxidative Stress and Mitochondrial Dysfunction in Chronic Kidney Disease: From Molecular Mechanisms to Biomarkers and Targeted Therapies

Chronic kidney disease (CKD) represents a major global health challenge, affecting more than 10% of the population and contributing substantially to morbidity and premature mortality. Growing evidence identifies oxidative stress and mitochondrial dysfunction as central drivers of renal injury and disease progression across diverse etiologies. The kidney is one of the most mitochondria-rich organs in the body, reflecting the high bioenergetic demands required for tubular reabsorption and metabolic homeostasis. Disruption of mitochondrial oxidative phosphorylation, excessive production of reactive oxygen species (ROS), and impaired mitochondrial quality control mechanisms promote tubular injury, inflammation, and fibrosis. In particular, dysfunction of the electron transport chain, activation of NADPH oxidase isoforms—especially NOX4—and alterations in mitochondrial dynamics create a vicious cycle of oxidative damage and bioenergetic failure. Emerging evidence highlights the importance of mitochondrial quality control pathways, including fusion–fission balance, PINK1/Parkin-mediated mitophagy, and mitochondrial biogenesis regulated by PGC-1α and TFAM. Additional mechanisms include ferroptosis, epigenetic regulation, mitochondrial DNA-mediated innate immune activation, and Na+/K+-ATPase-linked redox signaling. At the translational level, redox and mitochondrial biomarkers and targeted therapies are biologically compelling, but the evidence is uneven: most candidate biomarkers remain insufficiently standardized, and direct mitochondria-targeted interventions are supported predominantly by preclinical studies or small human proof-of-concept trials. This review therefore emphasizes not only mechanistic advances but also conflicting findings, model limitations, and the barriers that currently separate experimental efficacy from clinically meaningful CKD outcomes.

Dapagliflozin attenuates cellular senescence and mitochondrial dysfunction in diabetic kidney disease: potential involvement of AMPK/Sirt3 signaling.

Cellular senescence contributes to the pathology of diabetic kidney disease (DKD). Besides, mitochondrial dysfunction and cellular senescence are closely associated pathological processes that may influence one another during kidney injury progression. Dapagliflozin has demonstrated its renal protective benefits independent of the glucose-lowering effects, yet whether it acts via modulating cellular senescence is poorly understood. The design of our study is to explore the potential renal protective mechanism of dapagliflozin, focusing on cellular senescence and mitochondrial function. The streptozotocin-induced diabetic mice and high glucose-treated human renal tubular epithelial (HK-2) cells were used to achieve the purpose. We also employed Compound C and Sirt3 knockdown by small interfering RNA transfection to examine dapagliflozin's effect on AMPK/Sirt3 signalling pathway in HK-2 cell experiments. Dapagliflozin reduced the expression of renal senescence markers in both in vivo and in vitro experiments. Concurrently, dapagliflozin improved mitochondrial function, with evidence in mitochondrial membrane potential restoration, mitochondrial dynamics, and mitochondrial reactive oxygen species reduction, and lowered the levels of senescence-associated secretory phenotypes. Mechanistically, AMPK phosphorylation and Sirt3 expression level were attenuated by AMPK inhibitor compound C, which consequently attenuated dapagliflozin-mediated protective effects. Knockdown of Sirt3 in HK-2 cells substantially reduced dapagliflozin's improvements on mitochondrial function and its protective effects against cellular senescence, thereby reversing its alleviation of kidney function. Dapagliflozin treatment attenuated renal cellular senescence and improved mitochondrial function in DKD. Our findings support the involvement of AMPK/Sirt3 signaling in these renoprotective effects, as evidenced by the attenuation of dapagliflozin-mediated protection following AMPK inhibition and knockdown of Sirt3.

BRD2-Mediated TGR5 Destabilization Impairs Fatty Acid Oxidation and Drives Tubular Ferroptosis in Diabetic Kidney Injury.

Diabetic kidney injury is characterized by metabolic dysregulation, mitochondrial dysfunction, and tubular lipotoxicity; however, the molecular mechanisms integrating these pathological hallmarks remain incompletely elucidated. Here, we identify the epigenetic reader BRD2 as a pivotal regulator of renal tubular fatty acid oxidation (FAO) and ferroptosis. In streptozotocin-induced diabetic mice, BRD2 expression was progressively upregulated specifically in renal tubules, temporally coinciding with the onset and progression of tubular injury. Tubule-specific genetic ablation of Brd2 markedly attenuated diabetic nephropathy, as demonstrated by significant reductions in albuminuria, preservation of creatinine clearance, and amelioration of histopathological abnormalities including tubular atrophy, interstitial fibrosis, and lipid droplet accumulation. Mechanistically, BRD2 deficiency enhanced tubular FAO flux, reduced intracellular lipid accumulation, and suppressed ferroptosis, as evidenced by increased GPX4 and SLC7A11 protein levels, decreased ACSL4 expression, and diminished lipid peroxidation. Notably, BRD2 promoted the proteasome-dependent degradation of the bile acid receptor TGR5 without affecting its transcription, thereby reducing TGR5 protein abundance. Critically, tubule-selective knockdown of Tgr5 fully reversed the renoprotective, metabolic, and anti-ferroptotic benefits conferred by Brd2 deletion, leading to re-emergence of lipid overload and FAO suppression. Conversely, pharmacological activation of TGR5 with the selective agonist INT-777 rescued ferroptosis and restored FAO function in human proximal tubular cells overexpressing BRD2. Collectively, these findings delineate a BRD2-TGR5-FAO signaling axis as a central pathogenic driver of tubular lipotoxicity and ferroptosis in diabetic kidney injury, and position BRD2 inhibition as a mechanistically grounded therapeutic strategy for diabetic kidney disease.