TGF-β in chronic kidney disease: a controversy for decades

Chronic kidney disease (CKD) is characterized by persistent inflammation, maladaptive repair and progressive renal fibrosis, yet therapeutic strategies capable of effectively targeting these interconnected processes remain limited. Transforming growth factor-β1 (TGF-β1) is a central mediator of renal fibrosis but also exerts essential immunoregulatory and tissue-protective functions, creating a fundamental therapeutic paradox. Emerging evidence indicates that these divergent effects are determined not simply by TGF-β1 abundance, but by its cellular source and target, spatial and temporal context, interactions with other signaling pathways, and the transcriptional cofactors that determine downstream gene expression. This context dependence may partly explain why systemic TGF-β neutralization has shown limited clinical efficacy despite compelling preclinical evidence. In this Review, we discuss the cell-specific and stage-dependent functions of TGF-β1 in CKD, controversies surrounding the cellular origins of renal myofibroblasts, and the integration of TGF-β signaling with some signaling pathways. We further examine lessons from clinical trials and emerging therapeutic approaches designed to selectively modulate pathological TGF-β signaling, including regulation of latent TGF-β activation, receptor and Smad signaling, transcriptional cofactors, tissue-targeted delivery, and gene- and cell-based strategies. Particular attention is given to transcriptional partner selection as a mechanism of signal reprogramming. The β-catenin–TCF/FOXO1 axis provides a proof of concept whereby redirecting β-catenin from profibrotic TCF-dependent transcription toward FOXO1-associated anti-inflammatory and reparative programs may preserve beneficial TGF-β functions while limiting fibrosis. We propose that future TGF-β-targeted therapy should move beyond global pathway inhibition toward spatially, temporally and molecularly informed signal reprogramming, supported by biomarker-guided patient stratification and emerging single-cell and spatial technologies. Such precision modulation may provide a more rational strategy to suppress pathological fibrosis while preserving immune homeostasis and regenerative capacity in CKD.