Thymosin beta 4: An emerging therapeutic candidate for kidney diseases

Over the past decades, the escalating global burden of kidney disease has underscored an urgent need for innovative therapeutic strategies. Thymosin β4 (Tβ4), a highly conserved 43-amino-acid peptide encoded by the X-linked TMSB4x gene, is the predominant β-thymosin in mammalian cells and a multifunctional regulator of cellular homeostasis. Once considered mainly an actin-sequestering molecule, Tβ4 and its N-terminal metabolite N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) now emerge as dynamic mediators of renal injury and repair. In this review, we synthesize current evidence on the Tβ4-Ac-SDKP axis. We map intra- and extracellular mechanisms and relevant signaling pathways, delineate cell-type and spatial expression across glomerular and tubular compartments, and critically evaluate its renoprotective efficacy-including cytoprotection, anti-inflammatory and antifibrotic actions-across models of acute and chronic kidney injury. To reconcile disparate findings, we propose conceptual frameworks that consider bidirectional effects on fibrosis and model-dependent mechanisms. Finally, translational opportunities are appraised with attention to pharmacokinetics, peptide stability and delivery strategies. Key challenges moving forward include validating efficacy in additional clinically relevant models, overcoming peptide instability and completing comprehensive safety assessments.