HNG

HNG, also called S14G-humanin or [Gly14]-humanin, is a 24-amino-acid synthetic analog of humanin, a mitochondrial-derived peptide (MDP). Mitochondrial-derived peptides are short signals produced from mitochondria, the energy-producing compartments of cells, and humanin is among the best studied. The Ser14Gly substitution gives HNG roughly 1,000 times the cytoprotective potency of native humanin in cell-based oxygen-glucose deprivation work ¹.

HNG acts as a broad-spectrum cytoprotectant. In animal and cell models it reduces oxidative stress, blocks several forms of programmed cell death, and preserves mitochondrial energy production ¹. Researchers have tested it across neuroprotection, cardiac ischemia, kidney injury, chemotherapy toxicity, and reproductive damage models ⁶. Every published efficacy finding remains preclinical; no human interventional trial has been reported in the literature.

At the cell surface, HNG engages FPRL1 (formyl peptide receptor-like 1), a G-protein-coupled receptor. Knocking down FPRL1 or blocking it removes HNG's protective and lysosomal-restorative effects in human endothelial cells ²⁶. The main downstream signal is PI3K/AKT, which reactivates JAK2/STAT3. Inhibitors of PI3K, AKT, or JAK2 each block HNG's anti-apoptotic and antioxidant actions in oxygen-glucose deprivation experiments ¹. A second PI3K/AKT branch inhibits GSK-3β, helping restore the balance between pro-survival Bcl-2 and pro-death Bax and caspase-3 signals ⁷.

HNG also converges on several damage pathways:

• Inflammation: it lowers NF-κB, TLR4, and NLRP3 inflammasome activity and reduces IL-1β and IL-18 ⁶.
• Necroptosis: it blocks mitochondrial BAX and Z-DNA/ZBP1 signaling in diabetic kidney injury ¹⁴.
• Ferroptosis: it raises Nrf2/GPX4 and glutathione while lowering reactive oxygen species and labile iron ¹⁹.
• Metabolism: it preserves SIRT6 under high glucose ²⁹, inhibits NAD(P)H oxidase ³², and activates PGC-1α/AMPK ¹⁷. It also suppresses plasma IGF-1 in mice, a pattern researchers call a calorie-restriction mimetic ¹⁶.

The strongest efficacy data come from acute injury models in rodents and one porcine study ¹⁰. Evidence is not uniform: two early Alzheimer's-related papers were retracted ⁴⁴, at least one memory model was negative ³⁴, and some renal function markers did not improve ¹³. Key findings include:

• Neuroprotection: HNG reduced infarct volume and inflammatory cytokines in a murine stroke model ⁶, improved neurological scores in intracerebral hemorrhage ⁷, and reduced lesion volume after traumatic brain injury ⁸. In AD-model mice, three months of treatment improved cognition and reduced amyloid plaques ⁴.
• Cardiac protection: a 2 mg/kg dose reduced infarct size after 60 minutes of ischemia in pigs, though the benefit was lost with longer ischemia ¹⁰. Mouse heart-failure and diabetic-cardiomyopathy models also show functional improvement ¹¹.
• Renal protection: in renal ischemia-reperfusion, HNG restored antioxidant enzymes and mitochondrial ATP while reducing apoptosis, though BUN and creatinine were unchanged ¹³. In diabetic nephropathy, it reduced albuminuria and tubular necroptosis ¹⁴.
• Reproductive and chemotherapy protection: HNG protected germ cells and white blood cells during cyclophosphamide and enhanced chemotherapy's anti-metastatic effect ¹⁶. It preserved ovarian function and litter size in premature ovarian insufficiency models ¹⁷, restored sperm parameters in a male subfertility model ¹⁹, and reduced fibrosis in an intrauterine-adhesion model ²⁰.
• Lung and airway inflammation: HNG reduced edema, neutrophil infiltration, and NLRP3 activation in acute lung injury ²³, and lowered Th2 cytokines in allergic asthma ²⁴.
• Metabolic and vascular models: it protected endothelial cells from high-glucose senescence and apoptosis ²⁹, reduced foam-cell cholesterol loading ²⁸, and improved glucose and lipids in gestational diabetes ³³.
• Bone and muscle: ex vivo rat and human growth-plate tissue showed protection from venetoclax toxicity ²¹. In human myotubes, HNG preserved myotube area under dexamethasone but did not restore fusion index or E3-ligase expression ²².

Published HNG dosing is entirely animal and cell based. Representative animal protocols include 2 mg/kg IV before reperfusion in renal ischemia ¹³, 2 mg/kg IV in a porcine myocardial infarct model ¹⁰, 3-6 mg/kg IP after LPS in acute lung injury ²³, 2.5-5 mg/kg IP for 16 days in allergic asthma ²⁴, 5 mg/kg/day IP for 21 days in intrauterine adhesions ²⁰, 10 mg/kg IP for 6 weeks in ovarian insufficiency ¹⁸, and chronic daily IP dosing for three months in AD-model mice ⁴.

Because no human trials exist, community research protocols are unvalidated and use much lower doses. Common patterns are 250-500 mcg subcutaneously once daily as a conservative starting range, 500 mcg-1 mg once daily as a standard range, and 2.5-5 mg three times weekly for some higher weekly schedules. Cycles usually run 8-12 weeks. The timeline below summarizes one standard community research pattern. These doses sit one to two orders of magnitude below the effective animal range after standard allometric scaling, so human exposure assumptions remain untested.

HNG is supplied as lyophilized powder and is conventionally reconstituted with bacteriostatic water for multi-dose research handling. The diluent should be dripped gently against the vial wall and the vial rolled, not shaken or vortexed. Dry powder is held at -20°C for long-term storage, protected from light and moisture; 2-8°C is acceptable for short-term handling. After reconstitution, store refrigerated and use within about 30 days, and do not refreeze ².

HNG is structurally more robust than native humanin. In aqueous buffer at 37°C it stays largely disordered and returns to its original structure on cooling, while parent humanin converts irreversibly to beta-sheet ². The calculator below handles concentration and volume calculations for standard HNG vial sizes.

No formal human drug-interaction studies exist, so the following comes from co-administration experiments and pathway-inhibitor work.

• Alkylating chemotherapy: in cyclophosphamide-treated mice, HNG protected white blood cells and germ cells while strengthening the chemotherapy's suppression of lung metastases ¹⁶. It also reversed cyclophosphamide gonadal toxicity in later models ¹⁷.
• BCL-2 inhibitors: ex vivo, HNG rescued venetoclax-suppressed bone growth in rat and human growth-plate tissue ²¹. Because HNG raises Bcl-2 and lowers Bax/caspase-3, concurrent use could theoretically blunt BCL-2 inhibition ⁷.
• Proteasome inhibitors: HNG was co-administered with bortezomib in a neonatal brachial plexus injury model, and the combination prevented muscle contractures where HNG alone was inert ³⁹.
• Glucocorticoids: in human myotubes, HNG preserved area under dexamethasone but did not fully restore fusion index or E3-ligase expression ²².
• Pathway inhibitors: experimental PI3K, AKT, JAK2, and tyrosine-kinase inhibitors have each abolished HNG's protective effects in model systems ¹. Clinical drugs in these classes could theoretically attenuate HNG activity.
• Glycemic agents: HNG lowered glucose and raised insulin in diabetic-pregnancy mice ³³, so additive glucose lowering with insulin or secretagogues is a theoretical consideration.
• Supplements: genistein is a tyrosine kinase inhibitor that blocked HNG neuroprotection in rats ⁵; high-dose soy isoflavones are therefore a theoretical attenuator. No coagulation interaction has been identified.

Direct combination data are limited but a few pairs stand out.

• HNG + necrostatin-1: in a mouse cerebral ischemia-reperfusion model, this necroptosis inhibitor synergized with HNG, reducing infarct area from 59.3% to 38.6% ³⁶.
• HNG + SS-31: a hybrid HNSS construct combining SS-31 and HNG restored mitochondrial function, reduced amyloid/tau pathology, and improved memory in triple-transgenic Alzheimer's model mice ⁴¹. Separate co-injection of the two peptides has not been tested.
• HNG vs MOTS-c: the only direct comparison is in human myotubes, where MOTS-c outperformed HNG against dexamethasone-induced atrophy on fusion index and E3-ligase markers, while HNG preserved myotube area and blunted STAT3 ²². No conflict is documented for combined use.
• Native humanin: HNG is roughly 1,000-fold more potent than unmodified humanin ², so using both is unlikely to add value.
• IGF-1 pathway: HNG suppresses plasma IGF-1 in mice ¹⁶, so IGF-1-raising peptides work in the opposite direction for anabolic goals.
• GLP-1 receptor agonists: no direct data exist; overlapping renal and metabolic protection in HNG's diabetic nephropathy model makes additive effects plausible but unstudied ¹⁴.

HNG is not FDA-approved for any indication and has no published human clinical trials; the evidence base remains preclinical ¹. It is not listed in DEA Schedules I-V, and the humanin family is unrelated to controlled substances. In the United States, HNG is not on the FDA 503A bulk-substances list, so compounding pharmacies lack a lawful bulk-substance pathway for it. No HNG-specific FDA or FTC enforcement actions are documented.

No marketing authorization exists in the EU, UK, Australia, Canada, or other major jurisdictions. Two early Alzheimer's-related HNG papers were retracted and should be excluded from evidence weighting ⁴⁴.

WADA has not assessed HNG in published literature, and there are no documented athlete sanctions. HNG's IGF-1 suppression ¹⁶ makes classic peptide-hormone classification unlikely, but the general S0 provision on non-approved substances could still apply.

No human safety data exist. Across published animal studies, HNG-treated groups showed no excess mortality, weight loss, or organ pathology versus vehicle controls at tested doses ⁷. The longest published exposure is three months of daily intraperitoneal treatment in mice ⁴.

• IGF-1 suppression: HNG suppresses plasma IGF-1 in mice, both alone and with cyclophosphamide, which researchers describe as a calorie-restriction-mimetic effect ¹⁶. The human significance is unquantified.
• Renal markers: a single 2 mg/kg IV dose neither improved nor worsened BUN and creatinine in rat renal ischemia-reperfusion ¹³.
• Muscle cells: in primary human myotubes, HNG preserved myotube area without impairing viability or differentiation ²².
• Community reports: anecdotal human reports are limited mostly to transient injection-site discomfort.

Relative cautions are all theoretical at this stage. HNG activates STAT3/ERK and inhibits ferroptosis, raising caution around active malignancy, although the mouse cyclophosphamide study showed enhanced metastatic suppression rather than tumor protection ¹⁶. Pregnancy, lactation, and pediatrics lack data. No coagulation interaction has been identified. Chronic effects beyond three months and the dose threshold for IGF-1 suppression in humans are unstudied.