Dihexa

Molecular identity

Sequence

N-hexanoyl-Tyr-Ile-(6)-aminohexanoic amide — a Tyr-Ile dipeptide core capped at the N-terminus by hexanoic acid and at the C-terminus by 6-aminohexanoic acid amide (C27H44N4O5, 504.7 g/mol; CAS 1401708-83-5)

Formula

C27H44N4O5

Molecular weight

504.7 g/mol

CAS

1401708-83-5

PubChem CID

129010512

What it acts on

• HGF/c-Met receptor axis — the cited work describes Dihexa as a synthetic HGF mimetic that dimerises with endogenous hepatocyte growth factor to form a functional ligand for the c-Met receptor, making it an amplifier of an existing signal rather than a receptor agonist in its own right.
• PI3K/Akt — in a transgenic Alzheimer's mouse model the compound activated PI3K/AKT signalling, and the PI3K inhibitor wortmannin reversed the reported anti-inflammatory and anti-apoptotic readouts, which is the paper's basis for placing this branch on the causal path.
• mTOR and MEK branches downstream of c-Met — in the zebrafish hair-cell work, co-treatment with inhibitors of Akt, TOR and MEK partially attenuated the protective effect, consistent with several parallel effectors rather than a single one.
• Brain renin–angiotensin system — the molecule is an analogue of angiotensin IV, the endogenous hexapeptide of the central RAS, and tissue Ang IV was reported to rise in treated mice relative to wild-type animals.
• Glial activation and cytokine balance — the same mouse study reports reduced astrocyte and microglial activation with lower IL-1β and TNF-α and higher IL-10, readouts that the PI3K inhibitor wortmannin reversed.

What the studies report

Each item below summarises the paper it is numbered to, written from that paper's own abstract. The badge says how the evidence was produced.

1. 1.
   reviewJ Am Acad Orthop Surg Glob Res Rev (2026)

   A 2026 narrative review of therapeutic peptides written from an orthopaedic perspective. Dihexa appears only in passing, grouped with selank and semax among neuroactive peptides the authors describe as acting on BDNF and HGF/c-Met pathways relevant to neuroplasticity; no primary data on the compound are presented. The review states explicitly that, although preclinical work is promising, clinical trials are currently lacking.

2. 2.
   animal modelBrain Sci (2021)

   A study in APP/PS1 transgenic mice — a genetic model of Alzheimer's disease — using several dose levels. The authors report restored spatial learning in the Morris water maze, more neuronal cells and higher synaptophysin expression on Nissl staining, reduced astrocyte and microglial activation, lower IL-1β and TNF-α with raised IL-10, and increased tissue Ang IV relative to wild-type animals. Causality is assigned to PI3K/AKT on the strength of a single pharmacological block — wortmannin reversed the anti-inflammatory and anti-apoptotic effects — and the entire result rests on one transgenic mouse line.

3. 3.
   animal modelAnn Med Surg (Lond) (2021)

   A rat sciatic nerve transection-repair study: ten groups of six to eight male Lewis rats comparing mesenchymal stem cells, G-CSF and Dihexa, alone and in combination, against vehicle over sixteen weeks. Sensory function returned to near-normal by eight weeks across all groups pooled, including controls, so it discriminates nothing; the significant motor gain on walking-footprint grading appeared only for stem cells combined with G-CSF or with Dihexa. The compound is therefore reported as an adjunct within a combination rather than as effective on its own, and the group sizes are small.

4. 4.
   animal modelFront Cell Neurosci (2015)

   A protection screen in the larval zebrafish lateral line, whose hair cells are homologous to mammalian inner-ear hair cells, using the aminoglycosides neomycin and gentamicin as the insult. A concentration–response relationship was established; pretreatment did not change how much fluorescently tagged gentamicin entered the cells, so the authors attribute protection to intracellular signalling rather than blocked entry. Co-treatment with the HGF antagonist 6-AH attenuated the protection, as did adding an amino group at the N-terminus; co-treatment with inhibitors of the downstream targets Akt, TOR and MEK attenuated it only partially, so part of the effect is left unexplained by the HGF cascade.

Used in research on