Transforming Growth Factor-ß Signaling in Glomerular Diseases: Mechanisms of Fibrosis and Therapeutic Perspectives.

BACKGROUND: Glomerular diseases are major drivers of chronic kidney disease (CKD) and end-stage renal failure worldwide. Transforming growth factor-β (TGF-β) is a central molecular regulator that integrates inflammatory, metabolic, and extracellular matrix remodeling pathways, thereby promoting renal fibrosis. SUMMARY: This review synthesizes current evidence regarding TGF-β in glomerular diseases, emphasizing its context-dependent networks across distinct compartments of the renal microenvironment. Canonical SMAD signaling coordinates transcription of profibrotic genes, while non-canonical pathways (MAPK, PI3K/AKT, and Rho GTPases) amplify inflammatory and metabolic signaling. Rather than a uniform signaling pathway, TGF-β is shaped by disease-specific triggers, driving podocyte injury, mesangial activation, and progressive fibrotic remodeling. Despite strong experimental support, global inhibition of TGF-β has shown limited clinical success due to its pleiotropic roles in immune regulation and tissue homeostasis. Therapeutic strategies focused on selective modulation of distinct components, including SMAD3 inhibition, microRNA-based interventions, and extracellular vesicle-mediated delivery systems, show promise in attenuating profibrotic signaling while preserving physiological functions. In parallel, advances in biomarker discovery and transcriptomic profiling support biomarker-guided patient stratification and precision-based therapeutic approaches. KEY MESSAGES: TGF-β signaling is a major regulator of fibrogenesis in glomerular diseases but exerts context-dependent effects. Selective targeting of pathogenic signaling nodes, rather than global inhibition, combined with biomarker-guided stratification, represents a more effective therapeutic strategy. CONCLUSION: TGF-β remains a compelling therapeutic target in glomerular diseases, and integrating selective pathway modulation with biomarker approaches may enable successful interventions to limit fibrosis and slow CKD progression.