The pathogenesis of renal fibrosis in chronic kidney disease (CKD) is critically driven by dysregulated transforming growth factor-β (TGF-β) signaling, wherein TGF-β1 activates Smad2/3 phosphorylation to induce epithelial-mesenchymal transition (EMT), stimulate collagen synthesis, and inhibit matrix degradation-processes synergistically amplified through crosstalk with Wnt and MAPK pathways. Smad3 phosphorylation levels correlate positively with fibrosis severity, while Smad7 inactivation disrupts signal regulation, exacerbating pathway hyperactivity. Oxidative stress and angiotensin II (Ang II) further aggravate the fibrotic microenvironment via inflammatory responses and reactive oxygen species (ROS) accumulation. Current therapeutic approaches focus on TGF-β/Smad pathway modulation, including neutralizing antibodies, integrin inhibitors, Smad3-specific antagonists, and non-coding RNA-based interventions, complemented by multitarget regulation through Traditional Chinese Medicine (TCM) components. A central challenge lies in the heterogeneous cellular responses of renal subpopulations to TGF-β/Smad signaling, necessitating integration of single-cell omics to resolve dynamic regulatory networks and development of cell type-specific delivery systems. Future studies must prioritize cross-target synergy to address precision therapy bottlenecks and enhance clinical translation of antifibrotic strategies.

Yudong Zhang, Xili Wu. Targeting TGF-β/Smad in Chronic Kidney Disease Fibrosis: Mechanisms and TCM Therapeutics. International Journal of Frontiers in Medicine(2025), Vol. 7, Issue 2: 82-89. https://doi.org/10.25236/IJFM.2025.070212.

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