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.
Abstract
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.
Exosomes have a high translational potential for the diagnosis and treatment of kidney diseases, and this review provides a roadmap for bridging preclinical findings to clinical practice.
Juan He, Jianan Feng, Jin Zhao et al.· Nephrology, Dialysis and Tra...· 0 citations
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.
Renal fibrosis is a common pathological process underlying the progression of various kidney diseases to end-stage renal disease. It is characterized by the activation of renal interstitial fibroblasts and excessive deposition of the extracellular matrix (ECM). Continued progression can lead to irreversible loss of renal function, but effective targeted therapies are currently lacking. In recent years, nuclear receptor 4A1 (NR4A1) has been shown to bidirectionally regulate renal fibrosis. Nuclear NR4A1 exerts anti-fibrotic effects by inhibiting pathways such as TGF-β/Smad and NF-κB. However, upon pathological stimulation, NR4A1 translocates to the cytoplasm and mitochondria, where it promotes fibrosis by activating the NLRP3 inflammasome and p38 MAPK signaling and inducing mitochondrial damage. Thus, the functional outcome of NR4A1 is highly dependent on its subcellular localization. This review focuses on the dual anti-fibrotic and pro-fibrotic mechanisms of NR4A1 in renal fibrosis. Based on the regulation of its subcellular localization shifts, we explore targeted intervention strategies aimed at precisely stabilizing its nuclear protective function while blocking pathological nuclear export, thereby providing new directions for treating renal fibrosis.
Xu Li, Yufeng Qiao· Frontiers in Pharmacology· 0 citations
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
ALKBH5, as an m6A demethylase, plays a crucial regulatory role in various kidney diseases such as acute kidney injury, chronic kidney disease, renal fibrosis and renal cell carcinoma. However, its function often exhibits contradictory effects: In renal fibrosis, ALKBH5 has been reported to both promote and suppress fibrogenesis, whereas in renal cell carcinoma most studies support an oncogenic role, but some clinical observations link ALKBH5 downregulation to poor prognosis. These contradictions may stem from differences in cell types, disease stages, and microenvironments. This manuscript systematically reviews the complex function of ALKBH5 in kidney diseases and its underlying mechanisms, explores its potential as a therapeutic target, evaluates its therapeutic potential, and highlights the need for cell- and pathology-specific strategies to enable precise intervention. Future research should focus on its cell and pathological background specificity to achieve precise intervention.
YiFeng Dong, Danqin Lu, Yiling Wei et al.· Journal of Cellular Biochemi...· 0 citations
Chronic kidney disease (CKD) represents a growing global public health challenge. Current treatments, including pharmacological therapy, immunosuppression, and renal replacement therapy, mainly aim to slow disease progression rather than restore damaged renal tissue, and their efficacy remains limited in many patients. Although stem cell-based therapies have shown regenerative potential, their clinical application is constrained by poor cell survival, limited engraftment, immunogenicity, and potential safety concerns. Stem cell-derived exosomes (SC-exosomes) have therefore attracted increasing attention as a potential cell-free therapeutic strategy. These nanoscale extracellular vesicles can transfer bioactive cargoes, including proteins, lipids, messenger RNAs (mRNAs), and microRNAs (miRNAs), to recipient cells and thereby mediate intercellular communication. Compared with parental stem cell transplantation, SC-exosomes may offer several advantages, including lower immunogenicity, reduced tumorigenic risk, relative stability, and the potential to cross certain biological barriers. This comprehensive review summarizes current research on SC-exosomes in renal diseases, with emphasis on their biological characteristics, therapeutic mechanisms, preclinical evidence, and translational challenges. SC-exosomes may contribute to renal repair by promoting cell survival and regeneration, suppressing inflammation, apoptosis, oxidative stress, and fibrosis, and modulating immune and microvascular responses. We also discuss their potential relevance in multiple renal conditions, including acute kidney injury (AKI), CKD, diabetic nephropathy (DN), and other kidney diseases, as well as the use of exosomal cargoes as candidate diagnostic or prognostic biomarkers. Finally, we outline emerging opportunities and unresolved challenges in this field, including engineered exosomes, targeted delivery, exosome heterogeneity, dose optimization, large-scale production, purification, quality control, and long-term safety. Further standardized preclinical studies and well-designed clinical trials are needed before SC-exosome-based approaches can be translated into routine clinical application.
Qikai Luo, Nan Yang, Yiwei Shang et al.· Stem Cell Research & The...· 0 citations