Dihexa: the angiotensin IV analogue, its research record and the 2025 retractions
Prepared by: Research Desk. Sources are linked for verification.
Published 25 October 2026
At a glance
- What it is: dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, also coded PNB-0408) is a modified fragment of the brain peptide angiotensin IV, designed to resist breakdown and cross the blood–brain barrier
- Where it came from: a Washington State University group described it in the Journal of Pharmacology and Experimental Therapeutics (JPET) in 2013 (McCoy et al., 2013)
- Proposed mechanism: enhancement of hepatocyte growth factor (HGF) signalling through its receptor, c-Met
- Record under review: JPET published expressions of concern on the 2013 and 2014 papers in 2021, and in April 2025 retracted the 2014 mechanism paper and two related 2011–2012 papers from the same group
- Evidence level: rodent and cell studies only; a PubMed search on 25 October 2026 found no published human trials of dihexa
From angiotensin IV to dihexa
Angiotensin IV is a six-amino-acid fragment (Val-Tyr-Ile-His-Pro-Phe) of the renin–angiotensin system. Rodent studies have linked it and close analogues, such as Nle1-angiotensin IV, with better performance on learning and memory tasks. A 2018 systematic review by Ho and Nation in Neuroscience & Biobehavioral Reviews identified 32 eligible experimental studies; in models of cognitive deficit, eight of nine found that angiotensin IV or its analogues (Nle1-angiotensin IV, dihexa and LVV-hemorphin-7) improved performance on spatial working memory and passive avoidance tasks. The review noted that these peptides appeared most effective when given directly into the brain's ventricles close to the time of learning or testing.
The practical problem was stability: native angiotensin IV is broken down quickly and does not cross biological barriers well. McCoy et al. (2013) started from the finding that the activity of Nle1-angiotensin IV lay in its first three residues, Nle-Tyr-Ile, and then modified both ends of that tripeptide. The end product, dihexa, carries a hexanoic acid cap at the N-terminus and an aminohexanoic amide at the C-terminus. The authors reported that it was orally active and blood–brain barrier permeant in rats, and that it improved water-maze performance in rats impaired with scopolamine and in aged rats while increasing synapse formation in hippocampal cultures. In 2021 JPET attached an expression of concern to this paper.
The HGF/c-Met mechanism and the 2025 retractions
The best-known claim about dihexa is that it works through HGF and c-Met, a growth factor system involved in cell survival, migration and the formation of new synapses. That claim rests mainly on Benoist et al. (2014), which reported that dihexa bound HGF with high affinity, increased c-Met phosphorylation in the presence of low HGF levels, and lost its effect in the water maze when an HGF antagonist was delivered into the brain.
The publication record of that work has changed:
- 2021: JPET issued expressions of concern on the 2013 and 2014 papers
- April 2025: JPET published a retraction notice for the 2014 mechanism paper
- Same issue: JPET also retracted two earlier papers from the group on angiotensin IV analogues as HGF/Met modifiers (2012) and on HGF dimerization-domain mimics (2011)
The PubMed records list the notices but not the reasons; the notices themselves should be read for those details. Reviews written before 2025 that describe dihexa as an HGF/c-Met activator, including Wright and Harding (2015) in the Journal of Alzheimer's Disease and Wright, Kawas and Harding (2015) in Progress in Neurobiology, cite this body of work. The second review also notes that the identity of the angiotensin IV (AT4) receptor was disputed, with another group proposing insulin-regulated aminopeptidase (IRAP) as the binding site.
Studies from other groups
Independent studies are few and mixed:
- Alzheimer's disease model mice: Sun et al. (2021), in Brain Sciences, gave dihexa orally to APP/PS1 transgenic mice and reported better Morris water maze performance, more neurons on Nissl staining, lower astrocyte and microglia activation, and changes in inflammatory cytokines. A PI3K inhibitor, wortmannin, blocked the anti-inflammatory and anti-apoptotic effects, which the authors linked to PI3K/AKT signalling
- Huntington's disease-like model rats: Wells et al. (2024), in the Journal of Huntington's Disease, randomised 40 male Wistar rats exposed to the mitochondrial toxin 3-nitropropionic acid. Over five weeks, PNB-0408 (dihexa) did not protect the rats from the motor, learning or memory deficits caused by the toxin
The wider HGF/MET field
Interest in the HGF/MET system as a target did not depend only on dihexa. Fosgonimeton (ATH-1017), a different small-molecule positive modulator of HGF/MET, was described in a 2023 Neurotherapeutics paper and taken into a phase 2/3 trial in mild-to-moderate Alzheimer's disease. The LIFT-AD results, reported by Porsteinsson et al. (2025), showed the trial did not meet its primary or secondary endpoints at week 26. In rodents, a 2025 Neurotrauma Reports study reported that an HGF/MET positive modulator restored working memory after repeated mild traumatic brain injury; the abstract does not name the compound.
These findings concern other molecules and cannot be transferred to dihexa, but they show where the target itself stands: promising in animal models, not yet confirmed in human trials.
Limitations of the evidence
- No human data: there are no published human trials of dihexa, so its safety and effects in people are unknown
- Retracted mechanism paper: the main published evidence for the HGF/c-Met mechanism was retracted in 2025, and the founding 2013 paper carries an expression of concern
- Concentrated authorship: most early work came from one group, several of whose members also listed a company affiliation
- Mixed replication: one independent mouse study reported positive findings and one rat study found no protective effect
- Model limits: scopolamine amnesia, aged rats and transgenic mice each capture only part of human memory disorders
Key terms
- Angiotensin IV: a six-residue fragment of angiotensin II produced in the brain and other tissues
- HGF/c-Met: hepatocyte growth factor and its tyrosine kinase receptor, involved in cell growth, migration and synapse formation
- Expression of concern: a journal notice that flags possible problems with a paper while questions are investigated
- Retraction: formal withdrawal of a published paper by the journal; the paper stays visible but should not be relied on
Supplier
Purita is a store that sells peptides for laboratory research use only. It does not list dihexa; its neurological category lists research peptides such as Semax, Selank and DSIP, labelled for research use only and not for human or animal administration.
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- Semax: the ACTH(4-7)-Pro-Gly-Pro peptide and its research record
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