The thymosin family: thymosin alpha-1, thymosin beta-4 and TB-500
Thymosin alpha-1 and thymosin beta-4 share a name and an origin story but differ in structure, biology and evidence; TB-500 is a third thing.
Thymosin beta-4 was sequenced in 1981 as a 43-residue polypeptide isolated from calf thymus and described as one of several peptides present in "thymosin fraction 5" 1. Thymosin alpha-1 was described by Allan Goldstein in 1972 2. Three names circulate in research settings: thymosin alpha-1, thymosin beta-4 and TB-500 1,2,3.
Thymosin alpha-1
Thymosin alpha-1 is a 28-amino-acid peptide with an acetylated N-terminus and a mass of about 3,109 daltons 4. It is produced in vivo by cleavage of a larger precursor, prothymosin alpha, in diverse mammalian tissues 2. Research has centred on the immune system: a review reported that it primed dendritic cells for antifungal Th1 resistance through Toll-like receptor and MyD88-dependent signalling, and activated plasmacytoid dendritic cells through TLR9, with protective effects in mouse infection models 2.
The synthetic form, thymalfasin, was licensed for commercial development outside the United States and Europe in the early 1990s, and the sponsor reported approvals in more than 30 countries 5. A search of Drugs@FDA for thymalfasin returned no application 6. In the TESTS phase 3 trial in 1,106 adults with sepsis in China, 28-day all-cause mortality was 23.4% with thymosin alpha-1 versus 24.1% with placebo (hazard ratio 0.99), and no secondary or safety outcome differed significantly 7. Early trials combined thymosin alpha-1 with interferon and chemotherapy in advanced lung cancer and melanoma, and with interferon in chronic hepatitis B and C 8. A 2026 Cochrane review of ten randomised trials in chronic hepatitis B concluded that the effects on mortality and adverse events were based on low or very low certainty evidence 9. A pilot trial in 49 hospitalised patients with COVID-19 was open-label and found a faster CD4+ T-cell increase in one subgroup without a significant difference in clinical recovery 10.
Thymosin beta-4
Thymosin beta-4 is a 43-amino-acid, N-terminally acetylated polypeptide 1 and the major actin-sequestering molecule in eukaryotic cells, found in essentially all cells and body fluids 11,12. Reviews have linked it to dermal and corneal wound healing, and proposed potential applications in repairing ulcerated tissues and after hypoxic injuries such as myocardial infarction and stroke 12. Specific regions of the molecule have been assigned activities: an N-terminal Ac-SDKP motif that generally blocks inflammation and reduces fibrosis, a 15-residue N-terminal region promoting cell survival, and a short sequence containing LKKTETQ, the central actin-binding domain, linked to angiogenesis, wound healing and cell migration 11.
In a 2004 study, thymosin beta-4 promoted cardiomyocyte migration and survival in culture and improved cardiac function after coronary ligation in mice 13. In humans, a small phase 2 trial of an eye-drop formulation in severe dry eye (nine patients, 18 eyes) reported significant improvements in some signs and symptoms compared with vehicle 14.
TB-500
TB-500 is not thymosin beta-4: a 2012 doping-control paper described it as a veterinary preparation whose key ingredient is the peptide LKKTETQ, residues 17 to 23 of thymosin beta-4, with artificial N-terminal acetylation 3. The same paper noted that TB-500 is "claimed" to promote endothelial differentiation, angiogenesis and keratinocyte migration, and its aim was to identify misuse in horses 3. Because the name is used loosely, any source making claims about "TB-500" should be checked for which sequence it actually means 3.
How they differ
| Feature | Thymosin alpha-1 | Thymosin beta-4 | TB-500 |
|---|---|---|---|
| Structure | 28 amino acids, N-acetylated 4 | 43 amino acids, N-acetylated 1 | Acetylated LKKTETQ heptapeptide 3 |
| Origin | Cleaved from prothymosin alpha 2 | Ubiquitous actin-sequestering protein 11 | Synthetic version of residues 17 to 23 of thymosin beta-4 3 |
| Main research theme | Immune modulation via dendritic cells 2 | Actin binding, wound repair, cell survival 11,12 | Claimed angiogenesis and cell migration activity 3 |
| Human trial data | Phase 3 sepsis trial and hepatitis B randomised trials 7,9 | Small phase 2 dry-eye trial 14 | No controlled human trial identified in the sources reviewed 3 |
| WADA status | Not named in the sources reviewed 15 | Prohibited as thymosin-beta-4 and its derivatives 15 | Named as an example derivative 15 |
Key points
- Thymosin alpha-1 and beta-4 are distinct peptides of 28 and 43 residues that share a historical name 1,4.
- Thymosin alpha-1 has been tested in human randomised trials, including a null primary outcome in a large sepsis trial 7,9.
- Thymosin beta-4 evidence is mainly preclinical, with one small phase 2 dry-eye trial 13,14.
- TB-500 refers to an acetylated fragment of thymosin beta-4 and should not be conflated with the full protein 3.
Frequently asked questions
Are thymosin alpha-1 and thymosin beta-4 the same peptide?
Is thymosin alpha-1 approved by the FDA?
What is TB-500?
Did thymosin alpha-1 reduce mortality in sepsis?
References
- 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 U S A. 1981
- Thymosin alpha1: an endogenous regulator of inflammation, immunity, and tolerance Ann N Y Acad Sci. 2007
- Doping control analysis of TB-500, a synthetic version of an active region of thymosin β₄, in equine urine and plasma by liquid chromatography-mass spectrometry J Chromatogr A. 2012
- Generation of mature Nα-terminal acetylated thymosin α 1 by cleavage of recombinant prothymosin α ScientificWorldJournal. 2013
- Issues in pharmaceutical development of thymosin alpha1 from preclinical studies through marketing Ann N Y Acad Sci. 2007
- Drugs@FDA search for thymalfasin (no application returned) Drugs@FDA (openFDA). 2026
- The efficacy and safety of thymosin α1 for sepsis (TESTS): multicentre, double blinded, randomised, placebo controlled, phase 3 trial BMJ. 2025
- Thymosin alpha 1: from bench to bedside Ann N Y Acad Sci. 2007
- Thymosin-ɑ1 for people with chronic hepatitis B Cochrane Database Syst Rev. 2026
- A Pilot Trial of Thymalfasin (Thymosin-α-1) to Treat Hospitalized Patients With Hypoxemia and Lymphocytopenia Due to Coronavirus Disease 2019 Infection J Infect Dis. 2023
- Biological activities of thymosin beta4 defined by active sites in short peptide sequences FASEB J. 2010
- Thymosin beta4: actin-sequestering protein moonlights to repair injured tissues Trends Mol Med. 2005
- Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair Nature. 2004
- Thymosin β4 significantly improves signs and symptoms of severe dry eye in a phase 2 randomized trial Cornea. 2015
- World Anti-Doping Agency Prohibited List 2026 WADA. 2026
For research use only. Not for human or veterinary use. Not a drug, food, or dietary supplement. This article is educational and is not medical advice.
