Pharmacological targeting of kidney fibrosis: druggable mechanisms, translational models, and emerging antifibrotic therapies.

Kidney fibrosis is the final common pathological pathway through which chronic kidney disease progresses to end-stage kidney disease, yet therapies designed specifically to interrupt the core fibrotic process in the kidney are still lacking. This unmet need reflects the biological heterogeneity of kidney fibrosis, the context-dependent interplay among inflammatory, metabolic and mechanical signals, and the limited translational value of many conventional preclinical models. The mechanistic landscape has also broadened considerably beyond canonical transforming growth factor-β signaling, now encompassing immune-stromal crosstalk, metabolic rewiring, mechanotransduction, epigenetic reprogramming, and extracellular vesicle-mediated communication. These developments have brought several druggable nodes into view and may support more selective and durable antifibrotic interventions. At the same time, translational platforms including artificial intelligence-assisted in silico screening, patient-derived kidney organoids, bioengineered tissue systems, and refined animal models are changing how targets are discovered and pharmacologically validated. In this review, we examine emerging mechanisms that govern kidney fibrogenesis, with emphasis on therapeutic tractability, and consider how experimental models can improve target prioritization and drug development. We also summarize repurposed drugs, pathway-targeted agents, receptor-directed strategies, and cell-based approaches under preclinical or clinical evaluation. We close by discussing key barriers to clinical translation, including disease heterogeneity, inadequate biomarkers, and the need to balance antifibrotic efficacy with renal safety. A pharmacology driven framework that links mechanism, model, and patient stratification could help accelerate precision antifibrotic therapy for kidney disease.