Pharmacological Targeting of Kidney Fibrosis: Druggable Mechanisms, Translational Models, and Emerging Antifibrotic Therapies

Nanomedicine-Driven Precision Therapy for Renal Fibrosis: From Mechanistic Insights to Kidney-Targeted Interventions

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.

The dual role of exosomes in renal fibrosis and their potential for clinical translational applications

Abstract Renal fibrosis is the core pathological process in the progression of chronic kidney disease to its end stage. There is to date no novel therapeutic strategies that are both safe and efficient in reversing renal fibrosis in humans. Exosomes, as key mediators of intercellular communication, play significant regulatory roles in renal fibrosis. Translating mechanistic studies on exosome-mediated promotion or inhibition of renal fibrosis into clinically applicable anti-fibrotic strategies remains a challenging issue in this field. In this review, we systematically elucidate the distinct dual role of exosomes, highlighting how they function as either pro-fibrotic drivers or anti-fibrotic protectors depending on their cellular origin. In particular, we examine how renal tubular epithelial cell-derived exosomes promote renal fibrosis through multiple mechanisms by delivering specific cargoes—including miRNAs (e.g., miR-21, miR-19b-3p), mRNA (TGF-β1), and proteins (OPN, TNFAIP8)—via signaling pathways such as PTEN/Akt, NF-κB, and HIF-1α. Furthermore, we discuss exosome-based therapeutic strategies, focusing on the anti-fibrotic potential of mesenchymal stem cell-derived exosomes and targeted engineering strategies, such as drug loading and surface modification. Finally, we also summarize the value of urinary and blood exosomes as biomarkers in the diagnosis of renal fibrosis. In conclusion, by decoding the dual nature of exosomes, we offer a comprehensive framework to accelerate the clinical translation of these nanovesicles into precise diagnostics and targeted therapeutics.

Endothelial-to-Mesenchymal Transition in Chronic Kidney Disease: Mechanisms and Therapeutic Targets.

Natural Products Targeting Myocardial Fibrosis: Pharmacological Basis, Molecular Mechanisms and Translational Barriers

Myocardial fibrosis (MF) is a hallmark of pathological cardiac remodeling, driven by extracellular matrix (ECM) accumulation, fibroblast activation, and oxidative stress. Diverse natural products—notably alkaloids, flavonoids, terpenoids, and saponins—exhibit emerging antifibrotic potential. A comprehensive literature synthesis through July 2026 across PubMed, Web of Science, and Scopus categorized these agents by phytochemical class and disease models, delineating direct antifibrotic efficacy from indirect cardioprotection. Mechanistically, these compounds target TGF-β signaling, endothelial-to-mesenchymal transition (EndMT), autophagy/mitophagy, and ECM turnover. Robust preclinical evidence correlates with integrated histopathological assessment, specifically collagen and α-SMA quantification. However, translation remains impeded by model limitations, inadequate phytochemical standardization, and a critical paucity of clinical trials. Currently, no natural product holds clinical approval for MF. Future directives necessitate rigorous botanical authentication, pharmacokinetic/pharmacodynamic profiling, and adoption of human-relevant models, such as induced pluripotent stem cell-derived cardiomyocytes, to bridge the bench-to-bedside gap.

Exosomes in kidney disease: From Pathophysiology to Diagnostic and Therapeutic Tools.

BACKGROUND Kidney disease is a significant global public health and economic burden, with unmet clinical requirements for early diagnostic biomarkers and targeted therapies. Exosomes, nanoscale lipid bilayer vesicles that facilitate intercellular communication through bioactive cargo, have emerged as a promising translational tool for addressing these gaps. OBJECTIVE This review summarizes the classification, biological functions, technical workflows (isolation, characterization, and storage), and physiological/pathological roles of exosomes in kidney disease. It also emphasizes clinically actionable advances in exosome-based diagnosis and therapy and identifies translational barriers. METHODS This narrative review was conducted through a comprehensive literature search across PubMed, Web of Science, and Scopus databases up to April 2026. KEY FINDINGS Exosomes regulate renal pathological processes, including inflammation, oxidative stress, and fibrosis. Urinary/blood exosomal molecules are potential non-invasive biomarkers for acute/chronic kidney disease. Cell-derived exosomes demonstrate preclinical therapeutic efficacy for renal repairs. However, technical standardization and large-scale clinical validation remain significant challenges. CONCLUSION Exosomes have a high translational potential for the diagnosis and treatment of kidney diseases. Addressing standardization, validation, and regulatory challenges is crucial for clinical adoption, and this review provides a roadmap for bridging preclinical findings to clinical practice.

Mechanisms of Macrophage Glycolytic Reprogramming and Interventional Effects of Traditional Chinese Medicine on Renal Fibrosis

Abstract Renal fibrosis (RF) is a common pathological outcome of multiple chronic kidney diseases (CKDs), accompanied by substantial extracellular matrix (ECM) deposition and gradual decline of renal function. To date, no clinically viable treatment can reverse progressive renal fibrosis, making it critical to uncover its pathogenic mechanisms. Macrophages display remarkable phenotypic heterogeneity in fibrotic kidneys. Dramatic metabolic reprogramming occurs in these immune cells, with elevated aerobic glycolysis serving as a dominant trait. This metabolic switch not only sustains the energy demand of activated macrophages but also promotes the formation of pro-inflammatory and pro-fibrotic phenotypes. Apart from glycolysis, dysregulated glutaminolysis and lipid metabolism also interact with glycolysis to aggravate renal damage. TCM, owing to its multi-component and multi-target advantages, has shown favorable preclinical effects against renal fibrosis. A growing body of evidence suggests that TCM-derived monomers, formulas, and extracts may exert anti-fibrotic actions by modulating macrophage glycolytic reprogramming. However, the field faces prominent challenges. All relevant data are limited to preclinical studies, with no clinical validation to date. Most research evaluates glycolytic activity indirectly via the expression of metabolic enzymes rather than direct metabolic flux measurement. Additionally, the pharmacokinetics, toxicity, and translational potential of TCM components remain inadequately characterized. This narrative review elaborates the molecular mechanisms of macrophage glycolytic reprogramming in renal fibrosis and summarizes preclinical research on TCM interventions, while clarifying current research deficiencies and future directions.