Dihexa

Dihexa (N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, also coded PNB-0408) is a synthetic, peptide-derived compound developed from angiotensin IV. Its designers modified both ends of Nle-Tyr-Ile, the N-terminal core of the analog Nle¹-angiotensin IV, for metabolic stability and barrier permeability (McCoy et al., 2013). The same laboratory later proposed that Dihexa acts through hepatocyte growth factor (HGF) and its receptor c-Met, but that paper was retracted in 2025, and the 2013 paper carries a 2021 expression of concern.

Published work on Dihexa falls into six areas. Each summary below states the model used. The literature is preclinical, and the mechanism needs careful reading because of the retractions described below.

Design and first report

The developers reported that end modifications of the Nle-Tyr-Ile core kept the ability to reverse scopolamine-induced deficits in the Morris water maze and to augment hippocampal synaptogenesis, and that further changes to raise hydrophobicity produced Dihexa, which they described as able to cross the blood-brain barrier and active in scopolamine-treated and aged rats (McCoy et al., 2013). The journal attached an expression of concern to this paper in 2021. Models: rats, plus hippocampal synaptogenesis assays.

The HGF/c-Met mechanism and the 2025 retractions

A 2014 paper from the same laboratory reported that Dihexa binds HGF with high affinity, promotes c-Met phosphorylation at subthreshold HGF concentrations and induces hippocampal synaptogenesis, and that an HGF antagonist blocked its effect in the water maze (Benoist et al., 2014). The journal issued an expression of concern in 2021 and retracted the paper in 2025 (retraction notice, 2025).

A 2012 paper from the group describing the 6-AH family of angiotensin IV analogs as blockers of HGF dimerization was retracted at the same time (Kawas et al., 2012), as was a 2011 paper from the group on mimics of the HGF dimerization domain (Kawas et al., 2011). Later papers still describe Dihexa as an HGF/c-Met modulator, but the retracted work is not evidence. Models in the retracted papers: cell culture, hippocampal neurons and rodent behavior.

Rodent cognition and brain injury models

In APP/PS1 transgenic mice, an Alzheimer's disease model, Dihexa restored spatial learning in the Morris water maze, increased synaptophysin expression, reduced glial activation and pro-inflammatory cytokines, and activated PI3K/AKT signaling; the PI3K inhibitor wortmannin reversed its anti-inflammatory and anti-apoptotic effects (Sun et al., 2021).

In rats given repeated mild closed-head injuries, Dihexa infused into the brain ventricles rescued T-maze working memory at the highest amount tested, and a peptide antagonist of HGF dimerization blocked the effect (Martino et al., 2025). In rats exposed to 3-nitropropionic acid, a model of Huntington's disease-like symptoms, it did not protect against the motor or cognitive deficits (Wells et al., 2024). Models: mouse and rat.

Sensory hair cells in zebrafish

In the larval zebrafish lateral line, whose hair cells resemble those of the mammalian inner ear, Dihexa protected hair cells from neomycin and gentamicin, with optimal protection at 1 micromolar. It did not reduce gentamicin entry, and its protection was attenuated by the HGF antagonist 6-AH and by inhibitors of Akt, TOR and MEK (Uribe et al., 2015). Two of the four authors came from the developing laboratory, and the paper cites the two retracted papers for how 6-AH works and for HGF binding. Model: zebrafish larvae.

Peripheral nerve repair in rats

In a rat sciatic nerve transection and repair model, motor function at 8 to 16 weeks was significantly better when mesenchymal stem cells were given into the gastrocnemius muscle together with either G-CSF or Dihexa (Weiss et al., 2021). The significant motor effect was reported for the combinations, and one author came from the developing laboratory. Model: male Lewis rats.

A growth-factor substitute in stem-cell culture

Two stem-cell groups have used Dihexa as a small-molecule stand-in for HGF. A growth-factor-free protocol paired it with dexamethasone in the final stage of turning human pluripotent stem cells into functional hepatocyte-like cells (Siller et al., 2015).

A later protocol combined vitamin C, Dihexa and forskolin to replace growth factors during hepatic specification, and the resulting cells repopulated injured liver after transplantation into immune-deficient mice (Pan et al., 2022). In both, Dihexa was a culture reagent and was not given to animals. Model: human pluripotent stem cell culture, with a mouse transplant arm in the second study.