Introduction
The burden of chronic kidney disease (CKD) remains substantial, affecting approximately 9.5 % of the global population—nearly one in ten adults [1]. Projections suggest that the global population with kidney failure could approach 14.5 million by 2030 [2].This trend is closely linked to the rising rates of cardiometabolic disorders such as diabetes, hypertension and obesity [3]. The diagnosis of kidney diseases commonly marks the start of a lifelong course of medical management, with progressive organ dysfunction exerting profound impact on both quality of life and long-term outcomes [4]. Given this context, slowing disease progression as well as improving clinical outcomes are central priorities for nephrology. In response, Kidney Disease: Improving Global Outcomes (KDIGO) organization has emphasized the need for novel therapeutic strategies to improve patient care and long-term prognosis [5].
Thymosin β4 (Tβ4) is a 43–amino-acid peptide encoded by TMSB4x on the X chromosome and is among the most abundantly expressed β-thymosins in human tissues [6], comprising roughly 70–80 % of total thymosin content [7]. First purified and sequenced in 1981 [8], Tβ4 is expressed in numerous organs, supporting its broad therapeutic potential [9]. This profile is evidenced by preclinical studies demonstrating its pleiotropic functions, spanning the stimulation of angiogenesis, inhibition of apoptosis and fibrosis, attenuation of inflammation, and modulation of cell motility and differentiation [9]. These multifaceted activities have prompted investigation of Tβ4 across multiple contexts of organ injury and repair — from acute and chronic kidney injury [10], [11] to liver fibrosis [12], myocardial infarction [13], stroke [14], Alzheimer’s disease [15] and corneal or dermal wound healing [16], [17] — and it has also been explored in combination with engineered cell-based therapies as a potential means to treat complex disorders [18], [19], [20].
The emergence of Tβ4 as a candidate therapeutic is particularly compelling for nephrology: the rising prevalence of kidney disease and the lack of therapies targeting shared pathological drivers such as inflammation, fibrogenesis, extracellular-matrix (ECM) accumulation and tubular atrophy [21]. By modulating these key processes, therapeutics such as Tβ4 have the potential to slow disease progression and improve outcomes. Converging in vitro, preclinical and human data suggest that, in general, Tβ4 expression shows a downward trend in the context of kidney injury and disease. Consistent with this notion, preclinical studies in rodent models, such as diabetic nephropathy [22], [23], [24], [25], hypertensive kidney injury [26], [27], [28], unilateral ureteral obstruction (UUO) [29], [30] and lupus nephritis (LN) [31], [32], [33], have reported beneficial effects of exogenous Tβ4 or its metabolite N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) in nephrology.
In this review, we (i) comprehensively map the intracellular and extracellular molecular mechanisms of the Tβ4–Ac-SDKP axis, with an emphasis on signaling pathways that are relevant to renal physiology and pathology; (ii) delineate the cell-type– and spatially resolved expression patterns of endogenous Tβ4 in the kidney, integrating evidence from bulk, histological and single-cell studies; (iii) critically evaluate the renoprotective actions of the axis, including preservation of renal function, anti-inflammatory activity and antifibrotic effects; (iv)interrogate the sources of discrepant findings and advance unifying conceptual frameworks that accounts for context-dependent Tβ4 dynamics, bidirectional effects on fibrosis, and multiple routes to anti-inflammation, as well as model-specific differences in efficacy; (v) appraise translational opportunities informed by extant human data, focusing on pharmacokinetics, peptide stability and feasible delivery modalities, and we summarize potential adverse effects and safety considerations; and (vi) chart future research priorities, advocating for mechanistic dissection at cellular resolution, rigorous reconciliation of inconsistent results across models and diseases, and targeted validation in clinically relevant settings to accelerate translation.
Access through your organization
Check access to the full text by signing in through your organization.Access through your organization
Section snippets
Mechanistic insights into Tβ4 and its bioactive metabolite Ac-SDKP
Tβ4 is released from platelets, macrophages, and other cells upon tissue injury, and its diverse biological activities are determined by its 43-amino-acid sequence [34]. Distinct regions of the peptide confer different bioactivities: residues 1–4 are linked to anti-inflammatory and anti-fibrotic effects; residues 1–16 protect against cell injury and apoptosis; residues 17–22 (the actin-binding motif) regulate polymerization to promote angiogenesis and tissue repair; and residues 41–43 influence
Role of endogenous Tβ4 in the glomerulus
The glomerulus, a specialized capillary tuft, constitutes the fundamental filtration unit of the kidney. The glomerular filtration barrier is composed of endothelial cells, the glomerular basement membrane (GBM), and podocytes, and is supported by mesangial cells. Glomerular injury refers to damage affecting one or more of these structural components, thereby impairing the ability of the glomerulus to ultrafilter blood [145], [146]. Such injury manifests in diverse pathological phenotypes,
Therapeutic effects of endogenous and exogenous Tβ4 and its degradation product Ac-SDKP in disease models
In this section, we review the therapeutic roles of both endogenous and exogenous Tβ4 and its bioactive degradation product Ac-SDKP across various disease models, organized according to their biological effects (Fig. 6). Continuous delivery of Ac-SDKP via osmotic minipumps remains the most widely adopted approach, typically at doses of 800–1600 μg/kg/day [23], [24], [27], [28], [29], [31], [32], [77]. Within this range, Ac-SDKP has been shown to markedly elevate plasma concentrations and
Future directions and translational opportunities
From a therapeutic standpoint, Tβ4 is an attractive molecule for nephrology. Thymosins are grouped by isoelectric point (pI) into three classes — thymosin α (pI 3–5), thymosin β (pI 5–7) and thymosin γ (pI >7) — and 15 thymosin-β isoforms have been described, of which three occur in humans (Tβ4, Tβ10 and Tβ15) [7]. Tβ4 is the most extensively studied member of this family and has also secured the highest number of patents since 2018 [207]. As discussed above, abundant preclinical evidence
Conclusion
In summary, Tβ4 and its metabolite Ac-SDKP form an interrelated yet functionally distinct therapeutic axis. Multiple potential mechanisms of action have now been identified, and robust preclinical evidence across diverse rodent models of kidney disease supports their renoprotective potential. However, successful clinical translation will require: (i) enzymatic and genetic approaches capable of precisely dissecting the independent versus overlapping effects of Tβ4 and Ac-SDKP; (ii) development of
CRediT authorship contribution statement
Rui Zheng: Writing – review & editing, Supervision, Funding acquisition, Conceptualization. Hongquan Geng: Writing – review & editing, Supervision, Funding acquisition. Jiaxin Huang: Writing – review & editing, Writing – original draft. Huajie Di: Writing – original draft, Visualization, Investigation. Fei Ni: Investigation, Conceptualization. Dexin Zhang: Writing – review & editing, Conceptualization.
Funding
This work was partially supported by the National Natural Science Foundation of China [82470794, 82500860], and the Foundation of Children's Hospital of Fudan University [EKYX202423, EKSJD202416].
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors are grateful to the editor and the anonymous reviewers for their careful and constructive critiques. The authors also thank BioRender for providing the illustration platform used to prepare the figures. Figures were created with BioRender (www.biorender.com) under license.
References (236)
et al.
The potential of kidney transplantation to reduce mortality from chronic kidney disease: a global, cross-sectional, modelling study
Lancet Glob. Health
(2025) Y. Ying et al.
Thymosin β4 and actin: binding modes, biological functions and clinical applications
Curr. Protein Pept. Sci.
(2023) P.M. Zeng et al.
Thymosin beta 4 as an Alzheimer disease intervention target identified using human brain organoids
Stem Cell Rep.
(2025) G. Sosne et al.
Thymosin beta 4: A potential novel adjunct treatment for bacterial keratitis
Int. Immunopharmacol.
(2023) X. Zhang et al.
Enhancing fat graft survival: thymosin beta-4 facilitates mitochondrial transfer from ADSCs via tunneling nanotubes by upregulating the Rac/F-actin pathway
Free Radic. Biol. Med.
(2025) Y. Zuo et al.
Thymosin β4 and its degradation product, Ac-SDKP, are novel reparative factors in renal fibrosis
Kidney Int.
(2013) H. Tan et al.
Ac-SDKP ameliorates the progression of lupus nephritis in MRL/lpr mice
Int. Immunopharmacol.
(2012) S. Varland et al.
Actin post-translational modifications: the cinderella of cytoskeletal control
Trends Biochem. Sci.
(2019) E. Ballweber et al.
Plant profilin induces actin polymerization from actin: beta-thymosin complexes and competes directly with beta-thymosins and with negative co-operativity with DNase I for binding to actin
FEBS Lett.
(1998) E.M. De La Cruz et al.
Relating biochemistry and function in the myosin superfamily
Curr. Opin. Cell Biol.
(2004) T. Morita et al.
G-actin sequestering protein thymosin-β4 regulates the activity of myocardin-related transcription factor
Biochem. Biophys. Res. Commun.
(2013) A. Brieger et al.
Thymosin beta 4 expression and nuclear transport are regulated by hMLH1
Biochem. Biophys. Res. Commun.
(2007) R. Bednarek et al.
Ku80 as a novel receptor for thymosin beta4 that mediates its intracellular activity different from G-actin sequestering
J. Biol. Chem.
(2008) S.J. Lee et al.
Thymosin beta4 is involved in stabilin-2-mediated apoptotic cell engulfment
FEBS Lett.
(2008) C. Grillon et al.
Involvement of thymosin beta 4 and endoproteinase Asp-N in the biosynthesis of the tetrapeptide AcSerAspLysPro a regulator of the hematopoietic system
FEBS Lett.
(1990) S. Patel et al.
Renin-angiotensin-aldosterone (RAAS): The ubiquitous system for homeostasis and pathologies
Biomed. Pharmacother. = Biomedecine Pharmacother.
(2017) K. Inoue et al.
Quantification of N-acetyl-seryl-aspartyl-lysyl-proline in hemodialysis patients administered angiotensin-converting enzyme inhibitors by stable isotope dilution liquid chromatography-tandem mass spectrometry
J. Pharm. Biomed. Anal.
(2011) Q. Hong et al.
Modulation of transforming growth factor-β-induced kidney fibrosis by leucine-rich ⍺-2 glycoprotein-1
Kidney Int.
(2022) E. Vasilopoulou et al.
Loss of endogenous thymosin β(4) accelerates glomerular disease
Kidney Int.
(2016) H. Zhu et al.
Tenascin-C promotes acute kidney injury to chronic kidney disease progression by impairing tubular integrity via αvβ6 integrin signaling
Kidney Int.
(2020) G. Ternier et al.
Fibroblast Growth Factors: Roles and Emerging Therapeutic Applications
Curr. Drug Targets
(2025) G.J. Trusz
Fibroblast growth factor 21
Differ. Res. Biol. Divers.
(2024) H. Li et al.
Nanoparticle-mediated Klotho gene therapy prevents acute kidney injury to chronic kidney disease transition through regulating PPARα signaling in renal tubular epithelial cells
Biomaterials
(2025) GBD 2023 Disease and Injury and Risk Factor Collaborators
Burden of 375 diseases and injuries, risk-attributable burden of 88 risk factors, and healthy life expectancy in 204 countries and territories, including 660 subnational locations, 1990-2023: a systematic analysis for the Global Burden of Disease Study 2023
Lancet
(2025) M.E. Grams et al.
Chronic kidney disease
Ann. Intern. Med.
(2025) GBD 2021 Diseases and Injuries Collaborators
Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021
Lancet
(2024) 2024, Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group, KDIGO 2024 Clinical Practice Guideline for the... I. Bock-Marquette et al.
Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair
Nature
(2004) T.L. Low et al.
Complete amino acid sequence of bovine thymosin beta 4: a thymic hormone that induces terminal deoxynucleotidyl transferase activity in thymocyte populations
Proc. Natl. Acad. Sci.
(1981) Y. Xing et al.
Progress on the function and application of thymosin β4
Front. Endocrinol.
(2021) U. Aksu et al.
The protective effects of thymosin-β-4 in a rat model of ischemic acute kidney injury
J. Invest. Surg. Off. J. Acad. Surg. Res.
(2021) W.J. Mason et al.
The pathophysiological role of thymosin β4 in the kidney glomerulus
Int. J. Mol. Sci.
(2023) Z. Wang et al.
Mechanism of thymosin β4 in ameliorating liver fibrosis via the MAPK/NF-κB pathway
J. Biochem. Mol. Toxicol.
(2023) Y.L. Wang et al.
Thymosin β4 released from functionalized self-assembling peptide activates epicardium and enhances repair of infarcted myocardium
Theranostics
(2021) D.C. Morris et al.
Thymosin β4 for the treatment of acute stroke: neurorestorative or neuroprotective?
Expert Opin. Biol. Ther.
(2018) W.S. Yang et al.
Thymosin β4: potential to treat epidermolysis bullosa and other severe dermal injuries
Eur. J. Dermatol. EJD
(2019) Y. Ding et al.
Tβ4-engineered ADSC extracellular vesicles rescue cell senescence through separable microneedle patches for diabetic wound healing
Adv. Sci.
(2025) Y. Xi et al.
Injectable thymosin β4-modified hyaluronic acid hydrogel with exosomes for stem cell homing and neuronic-angiogenic-osteogenic coupled cranial repair
ACS Nano
(2025) E. Vasilopoulou et al.
The role of thymosin-β4 in kidney disease
Expert Opin. Biol. Ther.
(2015) J. Li et al.
Endothelial FGFR1 (Fibroblast Growth Factor Receptor 1) deficiency contributes differential fibrogenic effects in kidney and heart of diabetic mice
Hypertension
(2020) G. Castoldi et al.
Renal antifibrotic effect of N-acetyl-seryl-aspartyl-lysyl-proline in diabetic rats
Am. J. Nephrol.
(2013) K. Shibuya et al.
N-acetyl-seryl-aspartyl-lysyl-proline prevents renal insufficiency and mesangial matrix expansion in diabetic db/db mice
Diabetes
(2005) S.P. Srivastava et al.
Metabolic reprogramming by N-acetyl-seryl-aspartyl-lysyl-proline protects against diabetic kidney disease
Br. J. Pharmacol.
(2020) N. Kumar et al.
Thymosin β4 deficiency exacerbates renal and cardiac injury in angiotensin-II-induced hypertension
Hypertension
(2018) N.E. Rhaleb et al.
Renal protective effects of N-acetyl-Ser-Asp-Lys-Pro in deoxycorticosterone acetate-salt hypertensive mice
J. Hypertens.
(2011) T.D. Liao et al.
N-acetyl-seryl-aspartyl-lysyl-proline attenuates renal injury and dysfunction in hypertensive rats with reduced renal mass: council for high blood pressure research
Hypertension
(2010) M. Wang et al.
N-acetyl-seryl-aspartyl-lysyl-proline attenuates renal inflammation and tubulointerstitial fibrosis in rats
Int. J. Mol. Med.
(2010) P. Nakagawa et al.
Effects of N-acetyl-seryl-asparyl-lysyl-proline on blood pressure, renal damage, and mortality in systemic lupus erythematosus
Physiol. Rep.
(2017) T.D. Liao et al.
N-Acetyl-Seryl-Aspartyl-Lysyl-Proline: mechanisms of renal protection in mouse model of systemic lupus erythematosus
Am. J. Physiol. Ren. Physiol.
(2015) W. Wang et al.
The role of Tβ4-POP-Ac-SDKP axis in organ fibrosis
Int. J. Mol. Sci.
(2022)
1
H.J.Di and J.X.Huang contributed equally to this work and share first authorship.
© 2026 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.