Jul 2026· International Journal of Nanomedicine· Vol 21, pp. 1-38· 0 citations· 155 references
Medicine
TL;DR
This review systematically delineates the molecular landscape of renal fibrosis—with particular attention to emerging drivers such as epigenetic regulation and ferroptosis—and critically examines the translational hurdles of current strategies.
Abstract
Abstract Renal fibrosis acts as the convergent and irreversible pathological endpoint driving chronic kidney disease (CKD) to end-stage renal disease. Characterized by aberrant extracellular matrix (ECM) deposition and parenchymal architecture disintegration, this process is orchestrated by a dynamic multicellular network involving myofibroblast activation, metabolic reprogramming, and intricate crosstalk among signaling hubs like TGF-β/Smad and Wnt/β-catenin. While cornerstone therapies, such as renin-angiotensin system inhibitors (RASI) and sodium-glucose cotransporter 2 (SGLT2) inhibitors, retard progression, they face significant bottlenecks, notably the inability to reverse established fibrosis and the risk of off-target systemic toxicity. Nanomedicine offers a precision-engineering approach to surmount these physiological barriers. By leveraging spatiotemporal control, intelligent nanocarriers facilitate kidney-targeted delivery and microenvironment-responsive release, while functional nanomaterials exert intrinsic antioxidative and anti-fibrotic bioactivity to reshape the fibrotic niche. This review systematically delineates the molecular landscape of renal fibrosis—with particular attention to emerging drivers such as epigenetic regulation and ferroptosis—and critically examines the translational hurdles of current strategies. Integrating molecular insights with nanotechnological innovation, we discuss how nanomedicine can potentiate therapeutic efficacy and enable phenotype-specific precision interventions. Finally, we provide a forward-looking perspective on overcoming clinical barriers and constructing integrated theranostic and regenerative platforms.
This review examines emerging mechanisms that govern kidney fibrogenesis, with emphasis on therapeutic tractability, and considers how experimental models can improve target prioritization and drug development, and summarizes repurposed drugs, pathway-targeted agents, receptor-directed strategies and cell-based approaches under preclinical or clinical evaluation.
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.
Yan Liu, Lei Gao, Hao Xu et al.· Renal Failure· 0 citations
The cellular and molecular mechanisms of EndMT relevant to CKD are summarized, key regulatory pathways and pathway crosstalk are highlighted, and emerging pharmacological approaches to limit EndMT, preserve microvascular integrity, and attenuate renal fibrogenesis are discussed.
Abdul Khan, Pratheesh D. Mankuzhy, L. Thomas et al.· Kidney & Blood Pressure Rese...· 0 citations
This review systematically elucidates the distinct dual role of exosomes, highlighting how they function as either pro-fibrotic drivers or anti-fibrotic protectors depending on their cellular origin and offers a comprehensive framework to accelerate the clinical translation of these nanovesicles into precise diagnostics and targeted therapeutics.
Rui Hu, Jingyu Wang, Ying Yang et al.· Renal Failure· 0 citations
Chronic kidney disease (CKD) is sustained by a network of sterile inflammation, oxidative and metabolic stress, uremic toxin retention, gut barrier dysfunction, and maladaptive immune activation. These processes contribute to kidney fibrosis, cardiovascular injury, wasting, and excess mortality, but inflammatory biomarkers do not by themselves establish therapeutic causality. This narrative review integrates mechanistic and therapeutic evidence using an explicit three-layer translational hierarchy. Renin–angiotensin system inhibitors, sodium–glucose cotransporter-2 inhibitors, finerenone, and glucagon-like peptide-1 receptor agonists improve cardiorenal outcomes and have plausible anti-inflammatory actions, although inflammatory mediation remains unproven. Interleukin-1 blockade provides cardiovascular proof of principle and small dialysis feasibility data. Interleukin-6 ligand inhibition produces marked human target engagement; however, headline results from the completed phase 3 ZEUS trial showed no reduction in three-point major adverse cardiovascular events with ziltivekimab despite biomarker suppression, while serious infections were more frequent. POSIBIL6ESKD continues to test clazakizumab in inflamed dialysis patients. Direct NLRP3 inhibition has entered early human CKD development, whereas senescence-directed and microbiota-based approaches remain less mature. Future progress requires inflammatory endotyping, repeated biomarker assessment, mechanistically aligned outcomes, and rigorous infection surveillance. ZEUS underscores that pathway suppression must deliver clinical benefit beyond contemporary standard therapy.
A. Tsalouchos, P. Dattolo· Journal of Clinical Medicine· 0 citations
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.
Li Jiang, Shuang Guo, Yufei Zhang et al.· Seminars in Nephrology· 0 citations
