Hepcidin-25
Evidence: B+/C+ — Meaningful Human EvidenceAntimicrobial / Innate-Defense Peptides
Evidence Snapshot
What this grade covers
TWO SEPARATE EVIDENCE DOMAINS, never blended: Track A (iron-regulatory endocrine role) B+ -- landmark mechanistic study plus direct human clinical/observational evidence. Track B (direct antimicrobial role) C+ -- moderate primary in vitro evidence, form-resolved, with a binding non-membrane mechanistic constraint. Rusfertide/PTG-300 analogue-program data is ungraded/internal context only and never contributes to either grade.
Regulatory Context
Endogenous human hormone/peptide; no native Hepcidin-25 drug product approval record identified in this review. The synthetic hepcidin-mimetic rusfertide (PTG-300) is a distinct, separately-regulated analogue molecule in its own human clinical trial program (published Phase 2 REVIVE trial; Phase 3 VERIFY trial registered but not yet peer-reviewed-published) -- its data is never evidence for native Hepcidin-25.
Research Takeaway
Hepcidin-25 is a 25-residue, four-disulfide-bond peptide hormone encoded by the HAMP gene, predominantly expressed in the liver, originally isolated from human blood ultrafiltrate as 'LEAP-1'.
Evidence boundary: Identity/discovery finding; does not itself establish the iron-regulatory mechanism.
See all 7 evidence claims →Quick Summary
Hepcidin-25 is a 25-residue human peptide hormone with two separately-evidenced biological roles. Its best-established role is as the body's master iron-regulatory hormone, controlling iron availability via the ferroportin pathway. It also has a separate, less-studied direct antimicrobial role: unlike most antimicrobial peptides, its antibacterial activity depends on disulfide-stabilized DNA binding rather than membrane disruption, and the shorter Hepcidin-20 form was actually more potent than Hepcidin-25 in some antibacterial tests.
Mechanism & Research Overview
Hepcidin-25 is a 25-residue human peptide hormone with two separately-evidenced biological roles. Its best-established role is as the body's master iron-regulatory hormone, controlling iron availability via the ferroportin pathway. It also has a separate, less-studied direct antimicrobial role: unlike most antimicrobial peptides, its antibacterial activity depends on disulfide-stabilized DNA binding rather than membrane disruption, and the shorter Hepcidin-20 form was actually more potent than Hepcidin-25 in some antibacterial tests.
Evidence Claims
Individual scientific statements drawn from the sources cited below, each shown with the specific evidence boundary that statement does not establish.
Supported
Hepcidin-25 is a 25-residue, four-disulfide-bond peptide hormone encoded by the HAMP gene, predominantly expressed in the liver, originally isolated from human blood ultrafiltrate as 'LEAP-1'.
Does not establish
Evidence boundary: Identity/discovery finding; does not itself establish the iron-regulatory mechanism.
Sources: LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity
Supported
Hepcidin binds to the iron exporter ferroportin (SLC40A1) on cell surfaces, inducing its internalization and degradation and thereby decreasing cellular iron export -- the core mechanism of Hepcidin-25's role as the master iron-regulatory hormone.
Does not establish
Evidence boundary: Mechanistic/cell-culture study, not an in vivo human outcome trial. Unrelated to Hepcidin-25's separate, independently-graded antimicrobial role.
Sources: Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization
Supported
Urinary hepcidin excretion is markedly increased in patients with iron overload, infection, or inflammatory disease, and correlates with serum ferritin -- supporting hepcidin's role as a mediator of the anemia of inflammation.
Does not establish
Evidence boundary: Observational, not interventional.
Sources: Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein
Supported
Mature Hepcidin-25 shows dose-dependent antimicrobial activity against Gram-positive and Gram-negative bacteria and yeast in vitro.
Does not establish
Evidence boundary: Discovery-era characterization; does not itself specify the mechanism.
Sources: LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity
Supported
In directly compared in vitro assays against clinically relevant bacterial strains, Hepcidin-20 was active at lower concentrations than Hepcidin-25 in most conditions tested; bactericidal activity of both forms was substantially enhanced at acidic pH, and Hepcidin-25's activity was specifically enhanced by copper.
Does not establish
Evidence boundary: MANDATORY CAVEAT: this means Hepcidin-25 is NOT shown to be universally the most potent antimicrobial hepcidin form. Does not affect Track A's iron-regulatory dominance framing.
Supported
Hepcidin-25's antibacterial activity depends on its four disulfide bonds maintaining a beta-hairpin structure that binds DNA directly; a fully reduced or cysteine-free variant loses both DNA-binding and antibacterial activity, and no bacterial-membrane permeabilization was observed with native Hepcidin-25.
Does not establish
Evidence boundary: BINDING MECHANISTIC CONSTRAINT: must not be described as killing bacteria via membrane disruption.
Sources: Importance of the disulfide bridges in the antibacterial activity of human hepcidin
Supported
Hepcidin-25 induces reactive-oxygen-species-dependent, apoptosis-like killing of Candida albicans, with evidence that copper binding to its ATCUN motif contributes to this antifungal activity.
Does not establish
Evidence boundary: ANTIFUNGAL-SPECIFIC -- must not be generalized to the separate antibacterial mechanism above.
Sources: Human Antimicrobial Peptide Hepcidin 25-Induced Apoptosis in Candida albicans
Safety & Evidence Limitations
Considerations reported in the sources cited on this page — not a complete list of every possible risk, and not medical advice.
Safety Consideration
Excess hepcidin is mechanistically linked to anemia of inflammation in humans (elevated urinary/serum hepcidin correlates with iron overload, infection, and inflammatory disease). On the deficiency side, non-human comparator evidence is directly relevant: Usf2-knockout mice, which lack hepcidin gene expression entirely, develop severe multivisceral (tissue-wide) iron overload -- a mouse (COMPARATOR_MECHANISTIC, non-human) finding that illustrates hepcidin's necessity for normal iron homeostasis but does not itself constitute human evidence and must not be presented as such. Both the excess (human) and deficiency (mouse comparator) ends of this spectrum carry clinical relevance and must both be represented, kept clearly separated by species and evidence tier.Safety Consideration
The iron-regulatory (Track A) and antimicrobial (Track B) evidence domains rest on different studies and different mechanisms and must remain fully separately graded and discussed.Safety Consideration
A mandatory form/assay-specific caveat: Hepcidin-25 must not be presented as the universally dominant antimicrobial hepcidin form.Safety Consideration
Rusfertide is a distinct synthetic hepcidin-mimetic molecule with its own separate human clinical trial program (published Phase 2 REVIVE trial; Phase 3 VERIFY registered, not yet peer-reviewed-published). Its results must never be presented as native Hepcidin-25's own efficacy or safety evidence.
Research Areas Being Studied
Research areas discussed on this page reflect the Antimicrobial / Innate-Defense Peptides category and the sources cited below.
Findings Reported in Studies
Educational summary only — reported in cited studies, not a claim of proven benefit.
- Importance of the disulfide bridges in the antibacterial activity of human hepcidin (2012):
- Antimicrobial activity of human hepcidin 20 and 25 against clinically relevant bacterial strains: effect of copper and acidic pH (2010):
- Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization (2004):
- Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein (2003):
- LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity (2000):
Study Tables by Evidence Type
Human Studies & Clinical Data
| Title | Year | Population / Model | Dose / Duration / Finding | Safety Notes | Source |
|---|---|---|---|---|---|
| Importance of the disulfide bridges in the antibacterial activity of human hepcidin | 2012 | synthetic human Hepcidin-25 and cysteine-substituted variant, in vitro | Hepcidin-25's antibacterial activity depends on its four disulfide bonds maintaining a beta-hairpin structure that binds DNA directly; no membrane permeabilization was observed; a fully reduced/cysteine-free variant lost both DNA-binding and antibacterial activity. | ||
| Antimicrobial activity of human hepcidin 20 and 25 against clinically relevant bacterial strains: effect of copper and acidic pH | 2010 | in vitro bactericidal assay against clinical bacterial strains, form-resolved (Hepcidin-25 and Hepcidin-20 tested separately) | Hepcidin-20 was active at lower concentrations than Hepcidin-25 in most tested conditions; acidic pH enhanced both forms' activity; copper specifically enhanced Hepcidin-25's activity. | ||
| Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization | 2004 | human cultured cells | Hepcidin binds to ferroportin in cultured cells, causing its internalization and degradation and decreasing cellular iron export. | ||
| Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein | 2003 | human patients (iron overload, infection, inflammatory disease) | Urinary hepcidin excretion is greatly increased in patients with iron overload, infections, or inflammatory diseases, and correlates with serum ferritin. | ||
| LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity | 2000 | human blood ultrafiltrate, biochemical isolation; in vitro antimicrobial assay | Original isolation of the 25-residue, four-disulfide-bond peptide LEAP-1 (Hepcidin-25) from human blood ultrafiltrate, predominantly expressed in liver and heart, with dose-dependent antimicrobial activity against Gram-positive and Gram-negative bacteria and yeast. |
Animal / Cell / Preclinical Data
| Title | Year | Population / Model | Dose / Duration / Finding | Safety Notes | Source |
|---|---|---|---|---|---|
| Human Antimicrobial Peptide Hepcidin 25-Induced Apoptosis in Candida albicans | 2020 | in vitro Candida albicans assay | Hepcidin-25 induces ROS-dependent, apoptosis-like killing of Candida albicans; copper binding to its ATCUN motif contributes to this antifungal activity. | ||
| Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice | 2001 | USF2 knockout mice | Hepcidin-deficient (Usf2 knockout) mice develop severe multivisceral iron overload. |
Regulatory Documents & Official Trial Registries
No Regulatory Documents & Official Trial Registries Listed Yet
This section will be updated as sources are added.
Review Articles / Secondary Sources
| Title | Year | Population / Model | Dose / Duration / Finding | Safety Notes | Source |
|---|---|---|---|---|---|
| Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation | 2003 | narrative review | Reviews hepcidin's role as the iron-regulatory hormone and mediator of anemia of inflammation. |
Anecdotal Reported Patterns — Not Medical Advice
Anecdotal Reported Patterns — Not Medical Advice
Reported dosing patterns are included for educational context only. They are self-reported, unverified, not medical advice, and not instructions for human use. Community-submitted patterns are not yet available in this Phase 1 prototype; this section is a placeholder reserved for moderated, aggregated community data.
Lab Markers to Discuss With a Clinician
Educational topics only — not self-monitoring instructions.
FAQ
Disclaimer
Educational information only. This page summarizes published research on endogenous human Hepcidin-25 across two separate evidence domains (iron regulation and antimicrobial activity) and does not constitute medical advice, a treatment recommendation, or dosing guidance for any related substance.
Educational use only. This content is provided for informational and research-summary purposes only. It is not medical advice, not a treatment recommendation, not a dosing guide, and not a substitute for care from a licensed medical professional. Nothing here is intended to diagnose, treat, cure, prevent, or mitigate disease. Reported dosing patterns, when shown elsewhere on the site, must be labeled either as Study / Trial Dosing or Anecdotal Reported Patterns — Not Medical Advice. Community reports are self-reported, unverified, and not scientific proof.
Community-reported experiences, once enabled, must be displayed only as moderated, anonymized, or aggregated data. They are anecdotal, self-reported, unverified, and should never be presented as proof of safety, efficacy, or expected results.
Content status: Published. Last updated 2026-08-29.
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