pe
pep-05233 v1 CC-BY-SA-4.0

Hepcidin anticancer peptide

A short protein fragment studied in the lab for its ability to slow or kill cancer cells; experimental, not yet an approved drug.

statusbioassayed targetANTICANCER length56 aa refs3
anticancer
EARLY ENTRY This candidate is newly indexed — supporting evidence is still being added. Have a paper or data point? Contribute below.
status 2 / 5 · 0 verified on platform
prediction metrics boltz-2 2.2.1
ipTM0.000
pTM0.224
avg pLDDT53.9
ranking score0.476
STRUCTURE · PEP-05233 × ANTICANCER
ranking0.476
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RECEPTOR UNKNOWN
peptide conformation only · no target structure
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
sequence56 aa
151015202530354045505556
PPQTRQLTDLQTKD TAGAAAGLTPVLQR RRRDTHFPICIFCC GCCRKGTCGMCCRT
in the news 27 articles
Hypotheses5 directions▾ collapse

Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.

openupdated 2026-06-05

Could jamming the gate tumors use to move iron starve their growth?

Many tumors lean on a steady flow of iron to keep dividing, and they rely on a special gate to manage that iron. If this peptide can shut that gate and throw off the tumor cells' iron balance, it might slow their growth through a route very different from standard chemotherapy, and might be gentler on healthy cells because those cells depend on that gate far less.

The hypothesis
This hepcidin peptide binds and suppresses ferroportin-1 (SLC40A1) on cancer cells, depleting intracellular iron and thereby inhibiting iron-dependent proliferation independently of cytotoxic membrane disruption.
Why it’s plausible
Human hepcidin-25 is the endogenous ferroportin ligand: it binds the extracellular loop of SLC40A1 and triggers internalization and degradation, restricting cellular iron export. Many solid tumors overexpress ferroportin as an iron-release safety valve and are sensitive to iron starvation. The current card annotates the peptide only as 'anticancer' with no molecular target specified. Given that the peptide is derived from or structurally related to hepcidin and retains multiple cysteines compatible with the hepcidin binding hairpin, it plausibly retains ferroportin-binding capacity. The clinical-translation axis hits reference hepcidin inducers and inhibitors in clinical development (10.3390/ph11040127), and the immunogenicity hit explicitly describes hepcidin as an iron regulator.
Why it matters
If ferroportin suppression contributes to cancer cell killing, this peptide occupies a mechanistically distinct niche from conventional membrane-lytic anticancer peptides, and the therapeutic window may be wider because ferroportin is upregulated on tumor cells relative to most normal tissues.
Plausibility.58
Novelty.62
Impact.85
Basis · grounding2 papers · 1 computed/note
[1]
paper
Hepcidin plays a major role in innate immunity and iron regulation; canonical form identified in liver and plasma
doi: 10.1016/j.molimm.2007.11.007
[2]
paper
Hepcidin inducers and inhibitors are in clinical trials, confirming ferroportin axis is druggable
doi: 10.3390/ph11040127
[3]
sequenceCysteine-rich C-terminus with CCGCC and CGMCCRT motifs resembles the disulfide hairpin responsible for hepcidin-ferroportin contact
openupdated 2026-06-05

If the useful part of this molecule is only the back half, why build the whole thing?

Longer peptides are expensive and difficult to produce at scale. If only the shorter back portion of this molecule carries the active punch, a trimmed version could cost roughly half as much to manufacture, making it far more practical to test in large studies and eventually bring to patients.

The hypothesis
Truncating this peptide to the C-terminal 25-residue cysteine-rich domain (residues 32-56, spanning DTHFPICIFCCGCCRKGTCGMCCRT) while preserving the four disulfide bridges will recapitulate at least 80% of the anticancer potency of the full-length sequence at half the manufacturing cost.
Why it’s plausible
At 56 residues, this peptide is at the boundary identified in the manufacturing axis hit (10.1016/j.omto.2019.12.001) where SPPS cost becomes prohibitive for clinical development: natural anticancer peptides above 30 residues face 'greatly increased cost of synthetic production.' The canonical active hepcidin is 25 residues. If the N-terminal 28-31 residues function mainly as a pro-domain-like spacer rather than the killing module (as suggested by the structural separation of RRRR and the disulfide core), a 25-residue C-terminal fragment could retain full disulfide topology and activity at substantially reduced synthesis cost and with fewer aggregation issues.
Why it matters
A validated minimal active fragment would cut synthesis cost by roughly half and reduce the chain length below the SPPS efficiency threshold, enabling larger-scale screening and feasible clinical translation.
Plausibility.63
Novelty.42
Impact.72
Basis · grounding2 papers · 2 computed/notes
[1]
paper
Anticancer peptides above 30 amino acids face greatly increased synthetic cost; SPPS is efficient below 30 residues
doi: 10.1016/j.omto.2019.12.001
[2]
paper
Canonical human hepcidin is a 25-amino acid mature peptide; shorter forms of 20 and 22 residues have also been identified with retained activity
doi: 10.1016/j.molimm.2007.11.007
[3]
sequenceC-terminal 25 residues DTHFPICIFCCGCCRKGTCGMCCRT contain all 8 cysteines and the full disulfide potential of the peptide
[4]
structureLow global pTM 0.224 consistent with N-terminal region being disordered and potentially dispensable for folded core
openupdated 2026-06-05

Would this molecule go limp and useless if you removed the internal clips holding it in shape?

Some peptides only work when folded into a precise shape, held by internal sulfur bonds. If those bonds are essential here, making this drug requires a tricky extra manufacturing step, raising cost and complexity. Knowing this upfront helps researchers decide whether to invest in scaling it up or look for simpler alternatives.

The hypothesis
Disulfide bond formation among the eight cysteines in the C-terminal half of this peptide is required for stable beta-sheet folding and full anticancer potency, and the linear (reduced) form is substantially less active.
Why it’s plausible
The sequence encodes CCGCC and CGMCCRT motifs in the C-terminal region, providing eight cysteine residues in 56 total residues. This density and spacing is characteristic of the hepcidin disulfide ladder (four disulfide bridges in the canonical 25-residue mature human hepcidin). The Boltz-2 monomer prediction gives pTM = 0.224 and average pLDDT = 53.9, indicating a disordered ensemble in the absence of explicit disulfide constraints, consistent with the backbone being unable to fold without crosslinks. The selectivity axis hit from 10.1016/j.fsi.2016.01.038 directly reports that linear synthesized fish hepcidin peptides lose antibacterial potency relative to the native disulfide-bonded form.
Why it matters
If disulfide bonding is obligatory for activity, synthesis under oxidative refolding conditions is needed and the cost/complexity of manufacturing rises substantially; this shapes the feasibility of scale-up and the chemical space of analogs.
Plausibility.83
Novelty.18
Impact.60
Basis · grounding2 papers · 2 computed/notes
[1]
sequenceEight cysteines concentrated in PICIFCCGCCRKGTCGMCCRT at the C-terminus
[2]
structurepTM 0.224, avg pLDDT 53.9 for monomer with no disulfide constraints, indicating intrinsic disorder
[3]
paper
Linear synthesized hepcidin peptides without disulfide sulfur bond formation show weak antibacterial activity compared to native folded form
doi: 10.1016/j.fsi.2016.01.038
[4]
paper
Canonical hepcidin is a highly disulfide-bonded beta-sheet peptide; cysteine positions are conserved and essential
doi: 10.1016/j.molimm.2007.11.007
openupdated 2026-06-05

Could a single drug help shrink a tumor and fix the exhausting blood-iron problem many cancer patients live with?

Between 40 and 60 percent of cancer patients develop anemia that makes them exhausted and less able to tolerate treatment. If this peptide could tackle both the tumor and the iron imbalance driving that anemia, it would address two major problems at once, potentially improving quality of life and treatment outcomes for a large share of cancer patients.

The hypothesis
This hepcidin peptide suppresses hepcidin-resistant anemia of chronic disease in cancer patients by acting as an exogenous hepcidin agonist that corrects pathological iron maldistribution, independently of its direct anticancer cytotoxicity.
Why it’s plausible
Anemia of chronic disease, driven by inflammatory hepcidin upregulation and iron sequestration, paradoxically coexists with tumor-driven iron demand in cancer patients. A hepcidin-like peptide that mimics endogenous hepcidin's ferroportin-suppressing activity could restore iron homeostasis in patients where endogenous hepcidin signaling is blunted or dysregulated. The clinical-translation axis hit from 10.3390/ph11040127 explicitly discusses hepcidin analogs in clinical trials for iron-related conditions, and the phase I study of the anti-hepcidin Spiegelmer Lexaptepid is referenced in the same source, confirming the hepcidin axis is clinically validated. A molecule that both kills cancer cells and corrects cancer-associated anemia would offer additive benefit in solid tumor patients.
Why it matters
Cancer-associated anemia affects 40-60% of patients and reduces quality of life and chemotherapy tolerance. A peptide addressing both tumor biology and anemia from a single molecule would be a significant clinical advance over current hepcidin mimetics that lack anticancer activity.
Plausibility.37
Novelty.58
Impact.67
Basis · grounding2 papers · 1 computed/note
[1]
paper
Hepcidin inducers and inhibitors in clinical trials for anemia; Lexaptepid anti-hepcidin Spiegelmer studied in myeloma and lymphoma patients
doi: 10.3390/ph11040127
[2]
paper
Hepcidin plays a major role in innate immunity and iron regulation; suppresses ferroportin
doi: 10.1016/j.molimm.2007.11.007
[3]
sequenceCysteine-rich C-terminal domain matching hepcidin structural class that mediates ferroportin binding
openupdated 2026-06-05

Is a tiny positively charged patch the part that actually punches holes in cancer cells?

Cancer cells have a different surface charge than healthy cells, which some peptides exploit to punch holes in them. If a short four-unit stretch is doing most of that work here, researchers could build a much simpler, cheaper molecule around it. It also matters for safety: a membrane-punching drug and a receptor-targeting drug have very different side-effect profiles.

The hypothesis
The anticancer activity of this hepcidin peptide is primarily driven by its polyarginine stretch (RRRR at positions 29-32) disrupting negatively charged cancer cell membranes rather than by receptor-mediated targeting.
Why it’s plausible
The sequence contains a conspicuous RRRR motif at positions 29-32 embedded within the full 56-residue chain. Cationic charge clustering is a hallmark of membrane-lytic anticancer peptides that exploit the elevated phosphatidylserine and sialoglycoprotein content on cancer cell outer leaflets. Hepcidin itself is a cationic beta-sheet peptide relying on electrostatic membrane contact, and the axis hits confirm that native hepcidins exert bactericidal activity via membrane disruption. If the RRRR motif is the dominant killing unit, antiproliferative potency should be lost by charge-neutralizing substitutions (e.g., R-to-A) without affecting the disulfide core.
Why it matters
Distinguishing membrane-lytic from receptor-targeted mechanisms determines whether the peptide can be optimized by shortening to the active cationic module or requires the full disulfide scaffold, directly affecting manufacturability and selectivity strategy.
Plausibility.38
Novelty.33
Impact.53
Basis · grounding2 papers · 1 computed/note
[1]
sequenceRRRR motif at positions 29-32 of PPQTRQLTDLQTKDTAGAAAGLTPVLQRRRRDTHFPICIFCCGCCRKGTCGMCCRT
[2]
paper
Hepcidin hepcidins are cationic peptides; bactericidal activity attributed to membrane interaction
doi: 10.1007/s12602-017-9352-0
[3]
paper
Linear synthesized hepcidin peptides without disulfide bonds show reduced antibacterial activity, implicating cationic charge rather than fold in short-range killing
doi: 10.1016/j.fsi.2016.01.038
details expand to inspect
full evidence table1 metrics
metricvaluetool
ranking score 0.47616758942604065 boltz-2
3-letter notation
Pro-Pro-Gln-Thr-Arg-Gln-Leu-Thr-Asp-Leu-Gln-Thr-Lys-Asp-Thr-Ala-Gly-Ala-Ala-Ala-Gly-Leu-Thr-Pro-Val-Leu-Gln-Arg-Arg-Arg-Arg-Asp-Thr-His-Phe-Pro-Ile-Cys-Ile-Phe-Cys-Cys-Gly-Cys-Cys-Arg-Lys-Gly-Thr-Cys-Gly-Met-Cys-Cys-Arg-Thr
recipeboltz-2 2.2.1
parametervalue
modelboltz-2 2.2.1
weights
hardwarevast_v100_32gb
mlx version
python
random seed1
msa strategynone_monomer
runtime
predicted by
predicted at2026-05-23
citationbibtex
peptidemodel (2026). Hepcidin anticancer peptide (pep-05233, v1). PeptideModel. https://peptidemodel.com/card/pep-05233
@peptide{pep05233,
  sequence = {PPQTRQLTDLQTKDTAGAAAGLTPVLQRRRRDTHFPICIFCCGCCRKGTCGMCCRT},
  target   = {anticancer},
  author   = {peptidemodel},
  year     = {2026},
  status   = {bioassayed}
}
related peptides 5 by signal overlap
references 3 papers
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