Dihexa: Evidence and Publication Status

What is Dihexa?

Dihexa is a synthetic peptidomimetic developed from angiotensin IV. Angiotensin IV is a hexapeptide; that does not make Dihexa itself a six-amino-acid peptide. Our earlier description conflated the parent peptide with its modified analogue.

The literature reviewed here concerns experimental cell and animal work, together with a narrative review. It does not establish human benefit or safety. Publication notices materially change how the earlier findings should be presented.

Publication Status

2014 mechanism paper — retracted. Benoist and colleagues reported HGF/c-Met-dependent effects. The journal retracted that paper in 2025. We retain the reference to make the record transparent, but do not use it to establish mechanism, potency or efficacy. Read the retraction record.

2013 analogue study — expression of concern. The McCoy paper carries a formal editorial concern. This is distinct from a retraction, but its stability, potency and experimental-effect claims should not be repeated as settled findings. Read the concern record.

2015 review — background, not replication. A narrative review summarises a field; it is not a new experiment. Its presence in the bibliography does not independently validate the findings of the earlier papers.

Remaining Evidence

A 2021 study by Sun and colleagues used APP/PS1 mice, an experimental model used in Alzheimer’s disease research. It reported behavioural and tissue measurements and examined PI3K/AKT signalling. These are findings reported in a specific mouse study, not demonstrated outcomes in people. Read the study record.

That paper does not by itself establish selective HGF/c-Met activity, replicate every claim of the retracted work, or establish clinical benefit. A later publication is not a substitute for checking whether it actually tests the same claim.

What remains Uncertain

HGF/c-Met is a proposed mechanism in this literature. The withdrawn paper cannot establish that Dihexa selectively activates this pathway or acts without affecting other pathways. We have removed those assertions, along with the earlier claim that the studies establish the mechanism predicted by the chemistry.

A retraction does not prove every hypothesis about a compound false. It removes that paper as reliable supporting evidence. Each remaining claim needs its own appropriate evidence, and the cited preclinical literature does not establish human efficacy or safety.

Questions about the Evidence

Published References

1. McCoy AT, Benoist CC, Wright JW, et al. “Evaluation of metabolically stabilized angiotensin IV analogs as procognitive/antidementia agents.” The Journal of pharmacology and experimental therapeutics, 2013. PubMed
   Source review: Expression of concern. PubMed links an editorial concern notice (PMID 34551989) to this paper; interpret claims relying on it with that notice in view.
   View notice
2. Benoist CC, Kawas LH, Zhu M, et al. “The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system.” The Journal of pharmacology and experimental therapeutics, 2014. PubMed
   Source review: Retracted publication. PubMed records a 2025 retraction (PMID 40312093). This paper must not be treated as supporting evidence; claims relying on it require reassessment.
   View notice
3. Sun X, Deng Y, Fu X, et al. “AngIV-Analog Dihexa Rescues Cognitive Impairment and Recovers Memory in the APP/PS1 Mouse via the PI3K/AKT Signaling Pathway.” Brain sciences, 2021. PubMed
4. Wright JW, Harding JW. “The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease.” Journal of Alzheimer's disease : JAD, 2015. PubMed

Browse all Dihexa research on PubMed →