PwPepwise

HNG (Humanin S14G)

Energy & Cells

Potent humanin analog

HNG (Humanin S14G) is a synthetic, enhanced variant of Humanin — a small protective peptide naturally produced by mitochondria.

§Dosing at a glance

5 protocols · from the research
What it's forDoseHow oftenHowFor how long
Neuroprotection (stroke, rodent models)0.1 µgWeeklyIntraperitonealInjected into the abdominal cavity (research use).—
Cardioprotection (myocardial ischemia-reperfusion, rodent models)2 mg/kgWeekly—10 wks
Cardioprotection (porcine model)2 mg/kgWeekly——
Chemoprotection — bone growth / growth plate (mouse model)1 µgWeekly——
Chemoprotection — arthritis / glucocorticoid protection (mouse model)100 µg/kg/dayWeeklySubcutaneousInjected just under the skin, into the fat layer.14 days

Approximate values pulled from the research — double-check before dosing.

§01Summary

HNG (Humanin S14G) is a synthetic, enhanced variant of Humanin — a small protective peptide naturally produced by mitochondria and encoded within mitochondrial DNA. The substitution of glycine for serine at position 14 makes HNG significantly more potent than its parent peptide. In the body, HNG appears to shield cells from stress-induced death, particularly in tissues with high energy demands such as the brain, heart, and reproductive organs.

Across a broad range of preclinical studies, HNG has been reported to reduce brain injury following stroke1,2, protect heart muscle during heart attacks3, improve memory and reduce amyloid buildup in Alzheimer's disease models6, and preserve fertility-related cells during chemotherapy12,14. HNG may also support metabolic health by improving insulin signaling17 and reducing fat accumulation in liver tissue7. In an ex vivo human study, HNG improved sperm survival during cryopreservation9, and observational human data links lower endogenous Humanin levels to insulin resistance in polycystic ovary syndrome17. While the preclinical evidence base is broad and mechanistically well-characterized, human interventional trials are actively emerging, and the full clinical picture continues to develop.

This is the layperson summary. Mechanism, dosing, the evidence base, and the published literature are in the sections below — every claim links to its source.

§02In depth

HNG (Humanin S14G) is a 24-amino acid mitochondria-derived peptide (MDP) generated by substituting glycine for serine at position 14 of the native Humanin sequence. This single amino acid substitution confers significantly enhanced biological potency compared to wild-type Humanin. Humanin is encoded within the 16S ribosomal RNA gene of mitochondrial DNA and is secreted into the extracellular space, functioning as both an autocrine and paracrine signaling molecule.

HNG engages multiple receptor systems to exert its cytoprotective effects. At the plasma membrane, it signals through a tripartite receptor complex composed of CNTFR-α, WSX-1, and gp130, activating downstream JAK/STAT pathways including STAT3 phosphorylation, which appears to be the dominant mechanism in germ cell protection12. HNG also interacts with intracellular targets: it binds BAX to prevent mitochondrial outer membrane permeabilization and inhibits IGFBP-3-mediated nuclear pro-apoptotic signaling. Structure-function analogue studies suggest these pathways exhibit tissue-specific relative importance, with STAT3 signaling predominating in testicular protection and other pathways contributing variably in neuronal and cardiac contexts12.

In ischemic brain injury, HNG's neuroprotective mechanism has been specifically linked to PI3K/Akt pathway activation — HNG rapidly increases Akt phosphorylation in both neuronal cell cultures under oxygen-glucose deprivation and in vivo following middle cerebral artery occlusion. This effect is abolished by PI3K inhibitors (wortmannin) and Akt inhibitors (Akti-1/2), confirming pathway specificity2. In parallel, HNG selectively suppresses ERK phosphorylation without affecting JNK or p38 stress kinase activity, indicating targeted rather than broad anti-stress kinase modulation1.

In cardiac tissue, HNG activates AMPK and eNOS phosphorylation3, directly reduces mitochondrial complex I activity to limit electron transport chain-derived ROS generation under oxidative challenge11, and rapidly upregulates antioxidant enzymes catalase and glutathione peroxidase within 5 minutes through a non-genomic mechanism involving Abl and Arg non-receptor tyrosine kinases5. HNG also upregulates PGC-1α expression and enhances AMPK phosphorylation in ovarian granulosa cells, suggesting a mitochondrial biogenesis and energy-sensing role20. A newly characterized mechanism involves competitive binding to the IL-6 receptor alpha subunit, suppressing downstream IL-6/STAT3 pro-inflammatory signaling in lung vascular endothelial cells19 — a mechanism distinct from classical apoptosis-inhibitory pathways.

HNG's central nervous system effects include restoration of hippocampal long-term potentiation via CREB phosphorylation15 and reduction of amyloid pathology and neuroinflammation through chronic systemic administration6. Hepatic lipid metabolism is regulated via a central mechanism: systemic HNG increases hepatic microsomal triglyceride transfer protein (MTTP) activity and triglyceride secretion through a vagus nerve-dependent pathway, as demonstrated by the abolition of this effect following vagotomy7. IGF-1 suppression by HNG has also been observed, suggesting a potential caloric-restriction mimetic effect with systemic metabolic implications14.

§04Evidence & efficacy

Evidence base
239Studies
74Human
53Animal

HNG has demonstrated consistent preclinical efficacy across several therapeutic areas, with the most replicated evidence in neuroprotection and cardioprotection.

Neuroprotection / Stroke: In murine models, ICV pretreatment with HNG has been reported to reduce cerebral infarct volume by approximately 54% (from 56.2% to 26.1%)1, with the protective effect mediated through PI3K/Akt signaling2. A therapeutic window extending to at least 4 hours post-ischemia onset has been reported for ICV administration1. Combining HNG with the necroptosis inhibitor necrostatin-1 may further reduce infarct volume synergistically compared to either agent alone4.

Cardioprotection: In rodent ischemia-reperfusion models, HNG has been reported to reduce infarct size in a dose-dependent manner, with maximal effects at 2 mg/kg, while preserving left ventricular ejection fraction at one week post-ischemia3. These effects appear to be retained when administered at the time of reperfusion rather than only as pretreatment3. Mechanistically, HNG may protect cardiac mitochondria directly by decreasing complex I activity under oxidative stress11, and may enhance antioxidant defense through rapid activation of catalase and glutathione peroxidase5. In a porcine model — a more clinically translatable species — HNG at 2 mg/kg appeared to reduce infarct size following 60-minute ischemia, though this effect was not maintained at longer ischemic durations at the same dose16. In the setting of doxorubicin cardiotoxicity, the combination of HNG and dexrazoxane has been reported to significantly improve ejection fraction, reduce cardiac fibrosis, and preserve cardiac mass beyond either agent alone8.

Alzheimer's Disease / Cognitive Function: Chronic IP administration of HNG has been reported to improve spatial learning and memory, reduce cerebral amyloid plaque deposition, and attenuate neuroinflammation in transgenic AD mice with pre-existing pathology6. HNG has also been reported to dose-dependently reverse amyloid beta-induced inhibition of long-term potentiation in hippocampal slices, with restoration of phospho-CREB levels15.

Reproductive and Chemoprotective Applications: HNG has been reported to protect male germ cells and leukocytes from cyclophosphamide-induced apoptosis while simultaneously enhancing chemotherapy-induced suppression of lung metastases14. HNG may preserve bone growth in pediatric cancer treatment models without attenuating bortezomib's anticancer efficacy13. HNG appears to improve ovarian function in chemotherapy-induced premature ovarian insufficiency models, increasing primordial follicle counts and partially restoring litter size20.

Metabolic Effects: HNG may reduce hepatic triglyceride accumulation and visceral fat in high-fat diet models through a centrally mediated, vagus nerve-dependent mechanism7, and may alleviate insulin resistance in PCOS models through the IRS1/PI3K/Akt signaling pathway17.

Sepsis / ARDS: In a murine LPS model, HNG pretreatment has been reported to reduce inflammatory cytokine expression and protect lung architecture, with a proposed mechanism involving competitive binding to the IL-6 receptor alpha and suppression of IL-6/STAT3 signaling19.

§05Safety

Across the preclinical studies reviewed, HNG has demonstrated a consistently favorable tolerability profile. In rodent cardioprotection studies, HNG administered at 5 mg/kg/day intraperitoneally for 10 weeks — alone or in combination with dexrazoxane — showed no adverse effects on cardiac structure or function in healthy animals8. In the chemoprotection context, HNG at 100 µg/kg/day subcutaneously for 14 days appeared well-tolerated in mice without observable toxicity18. In the bortezomib bone growth study, HNG at 1 µg/mouse did not produce observable adverse effects13. In the sperm cryopreservation ex vivo human study, none of the tested concentrations (2–20 µM) produced detrimental effects on sperm cells9.

HNG has been reported to selectively protect normal tissues — including growth plate chondrocytes, germ cells, and leukocytes — without conferring protection to tumor cells in cancer models, and without interfering with anti-inflammatory activity of co-administered glucocorticoids13,14,18. This selectivity is a favorable safety feature in the context of combination therapy.

Human safety data from interventional dosing remains an active area of clinical investigation. Available human data is limited to observational measurements of endogenous Humanin levels17,19 and one ex vivo sperm study9. Formal toxicology, pharmacokinetics, maximum tolerated dose, and long-term safety studies in humans are underway as the clinical evidence base develops.

§06History

Humanin was first identified in 2001 by Hashimoto and colleagues while screening a cDNA library derived from the surviving neurons of an Alzheimer's disease patient's occipital lobe. The peptide was discovered through its ability to rescue neuronal cells from death induced by familial Alzheimer's disease-associated gene mutations — an unusual discovery context that immediately linked it to neurodegeneration. The finding that its coding sequence resided within mitochondrial 16S rRNA established Humanin as one of the first described mitochondria-derived peptides, a now-recognized class of bioactive signaling molecules.

HNG (S14G-Humanin), the glycine-substituted analogue with substantially greater potency than native Humanin, was developed shortly thereafter to support mechanistic and therapeutic research. By the mid-2000s, studies had established HNG's neuroprotective activity in stroke models1 and began delineating PI3K/Akt-dependent mechanisms2. From 2010 onward, the field expanded substantially, with landmark demonstrations of cardioprotection in murine ischemia-reperfusion models3 and subsequent mechanistic characterization of direct mitochondrial protective actions5,11. Research broadened through the 2010s to encompass metabolic regulation7, male and female reproductive protection during chemotherapy12,14,20, pediatric bone growth preservation13, and anti-inflammatory applications18,19. The first translational cardioprotection data in a porcine model was published in 202016. As of the mid-2020s, HNG continues to be actively investigated across neurology, cardiology, oncology, endocrinology, and reproductive medicine, with human observational data emerging and interventional clinical studies in development.

§07References