SHLP2 (Small Humanin-Like Peptide 2) — Safety, Research, Risks & Legal Status

Not medical advice. SHLP2 (Small Humanin-Like Peptide 2) is discussed here for informational and harm-reduction purposes only. We do not endorse use, and any dosing context is informational, not a protocol.

Also known as	Small Humanin-Like Peptide 2; SHLP-2; MT-RNR2-derived peptide
Category	Peptide (research chemical)
Molecular weight	3,017.54 Da
Length	26 amino acids (sequence: MGVKFFTLSTRFFPSVQRAVPLWTNS)
Gene of origin	MT-RNR2 (mitochondrial 16S rRNA region, mtDNA)
Primary receptor target	CXCR7 (EC50 ~0.97 µM in vitro)
Discovery / patent holder	Cohen Lab, University of Southern California; patent US8637470B2
Development stage	Preclinical only - in vitro and rodent models; no human trials registered
US legal status	Not FDA-approved. No Investigational New Drug (IND) application identified; no active clinical development program. SHLP2 is available commercially from research supply companies (e.g., Phoenix Pharmaceuticals, MedChemExpress, Isca Biochemicals) for in vitro and laboratory research use only. Not approved for human consumption. Not classified as a dietary supplement. The peptide sequence is covered by patent US8637470B2 and related USC-held patents. No federal scheduling or controlled-substance status; sold under standard research-chemical terms restricting human use.

What is SHLP2 (Small Humanin-Like Peptide 2)?

SHLP2 is a 26-amino acid mitochondrial-derived peptide (MDP) encoded within the MT-RNR2 gene (the mitochondrial 16S rRNA locus). It is one of six Small Humanin-Like Peptides (SHLP1-6) discovered by the Pinchas Cohen laboratory at the University of Southern California. Like its family members, SHLP2 is endogenously produced from mitochondrial DNA and circulates at low levels in the body. It is structurally related to humanin, the first MDP identified, and shares its general cytoprotective and metabolic biology. All current data are preclinical (cell culture and rodent models); no human studies have been conducted.

How it works

SHLP2 operates through several partially overlapping mechanisms, all characterized preclinically. It binds and activates the chemokine receptor CXCR7 (EC50 approximately 0.97 µM), inducing beta-arrestin recruitment and receptor internalization - a signaling pathway associated with cytoprotective and anti-inflammatory effects. It exhibits chaperone-like activity, inhibiting misfolding of amyloid-beta peptide and IAPP (islet amyloid polypeptide implicated in type 2 diabetes). At the mitochondrial level, it restores OXPHOS complex I-V protein expression, increases mitochondrial respiration and ATP production, elevates mitochondrial DNA copy number, and upregulates PGC-1alpha (a master regulator of mitochondrial biogenesis). Anti-apoptotic effects include reduction of activated caspase-3/7 and attenuation of reactive oxygen species. Centrally, in rodent hypothalamus, SHLP2 activates POMC neurons to suppress appetite and promote thermogenesis. Whether these mechanisms operate independently or converge remains unclear from available data.

Background & history

SHLP2 was discovered as part of a systematic search for additional humanin-like peptides encoded within the mitochondrial 16S rRNA gene (MT-RNR2). The Cohen laboratory at USC identified and characterized SHLP1-6 as a family, with foundational work published around 2017-2018. Patent protection for the small humanin-like peptide sequences was secured by USC (US8637470B2). The peptide entered commercial research supply catalogs as an in vitro tool compound. A 2023 Nature Communications study substantially advanced mechanistic understanding of SHLP2's metabolic role in the hypothalamus, representing the most detailed rodent in vivo characterization to date. No biotech or pharmaceutical company has publicly announced a clinical development program for SHLP2 as of mid-2025.

What the research says

SHLP2 remains a purely preclinical research molecule as of mid-2025. No clinical trials are registered on ClinicalTrials.gov. Published work spans three primary areas. First, in AMD-patient-derived retinal pigment epithelial (ARPE-19 cybrid) cells, SHLP2 restored oxidative phosphorylation (OXPHOS) complex protein levels and reduced cell death, suggesting relevance to age-related macular degeneration pathology (PubMed: "SHLP2 macular degeneration ARPE-19 cybrid"). Second, in a 2023 rodent energy-homeostasis study, SHLP2 administered centrally activated hypothalamic POMC (pro-opiomelanocortin) neurons, suppressed food intake, prevented high-fat-diet-induced obesity, and improved insulin sensitivity in mice (PubMed: "SHLP2 energy homeostasis hypothalamus POMC 2023"). Third, additional cell-culture work has demonstrated neuroprotective activity in Parkinson's-relevant models, protection of pre-osteoblasts against oxidative stress, and improved bioenergetics in pancreatic beta cells. No formal toxicology studies, pharmacokinetic data, or IND-enabling studies have been published. Researchers in primary literature explicitly note that further preclinical work is required before any human transition could be considered.

Reported effects

Neuroprotection in preclinical (cell culture) models relevant to Parkinson's disease and AMD - animal/in vitro only
Restoration of mitochondrial OXPHOS complex proteins and increased ATP production - in vitro only
Suppression of food intake and prevention of diet-induced obesity via hypothalamic POMC neuron activation - rodent only
Improved insulin sensitivity in high-fat-diet mouse models - rodent only
Anti-apoptotic activity (caspase-3/7 reduction) in stressed cell lines - in vitro only
Inhibition of amyloid-beta and IAPP misfolding (chaperone-like) - in vitro only
Protection of pre-osteoblasts against oxidative stress - in vitro only

Dosing & administration (informational)

No human dosing has been studied. In rodent metabolic experiments (mice, high-fat diet models), central or peripheral administration has been used at investigational doses described in primary literature; these figures are not translatable to human use. Literature ranges are reported here for informational and research-context purposes only and do not constitute a protocol, recommendation, or guidance for human use. Anyone considering any peptide for personal use should consult a licensed clinician. PubMed search "SHLP2 energy homeostasis hypothalamus" describes rodent administration parameters.

This is general research/context information, not medical advice or a recommended protocol.

Safety & side effects

No human safety data of any kind; risk profile in humans is entirely unknown
No formal toxicology studies (acute, subacute, chronic, genotoxicity) identified in published literature
No adverse effects reported in cell culture or rodent studies, but absence of reported harms does not establish safety for human use
Pharmacokinetics (oral bioavailability, half-life, distribution, metabolism, excretion) not characterized in humans or animals
As a mitochondrial signaling peptide with CXCR7 agonist activity, off-target immunomodulatory effects cannot be excluded without dedicated studies
IND-enabling safety package does not exist; no regulatory agency has reviewed a human-use dossier
Human use outside a supervised clinical trial context would constitute experimentation with an entirely uncharacterized safety profile

Drug & supplement interactions

N
o
h
u
m
a
n
p
h
a
r
m
a
c
o
k
i
n
e
t
i
c
o
r
p
h
a
r
m
a
c
o
d
y
n
a
m
i
c
i
n
t
e
r
a
c
t
i
o
n
d
a
t
a
e
x
i
s
t
.
T
h
e
o
r
e
t
i
c
a
l
c
o
n
s
i
d
e
r
a
t
i
o
n
s
b
a
s
e
d
o
n
m
e
c
h
a
n
i
s
m
i
n
c
l
u
d
e
:
p
o
t
e
n
t
i
a
l
a
d
d
i
t
i
v
e
o
r
c
o
m
p
e
t
i
n
g
e
f
f
e
c
t
s
w
i
t
h
o
t
h
e
r
C
X
C
R
7
l
i
g
a
n
d
s
(
e
.
g
.
,
C
X
C
L
1
2
/
S
D
F
-
1
,
C
X
C
L
1
1
)
;
p
o
s
s
i
b
l
e
s
y
n
e
r
g
y
o
r
i
n
t
e
r
f
e
r
e
n
c
e
w
i
t
h
o
t
h
e
r
m
i
t
o
c
h
o
n
d
r
i
a
l
-
t
a
r
g
e
t
e
d
c
o
m
p
o
u
n
d
s
o
r
P
G
C
-
1
a
l
p
h
a
m
o
d
u
l
a
t
o
r
s
;
u
n
k
n
o
w
n
i
n
t
e
r
a
c
t
i
o
n
s
w
i
t
h
G
L
P
-
1
r
e
c
e
p
t
o
r
a
g
o
n
i
s
t
s
o
r
o
t
h
e
r
a
p
p
e
t
i
t
e
-
s
u
p
p
r
e
s
s
i
n
g
a
g
e
n
t
s
g
i
v
e
n
o
v
e
r
l
a
p
p
i
n
g
h
y
p
o
t
h
a
l
a
m
i
c
t
a
r
g
e
t
s
i
n
r
o
d
e
n
t
m
o
d
e
l
s
.
A
l
l
o
f
t
h
e
a
b
o
v
e
i
s
s
p
e
c
u
l
a
t
i
v
e
e
x
t
r
a
p
o
l
a
t
i
o
n
f
r
o
m
p
r
e
c
l
i
n
i
c
a
l
m
e
c
h
a
n
i
s
m
;
n
o
i
n
t
e
r
a
c
t
i
o
n
s
t
u
d
i
e
s
h
a
v
e
b
e
e
n
c
o
n
d
u
c
t
e
d
.

Who should avoid it

Human self-administration - no safety profile established
Parenteral use outside a supervised clinical trial setting
Combination with other uncharacterized research peptides where additive unknown risks compound
Sourcing from unverified suppliers lacking purity documentation even for legitimate in vitro research
Inferring therapeutic dosing from rodent studies - cross-species translation is not validated for this compound

How it is commonly combined

No human stacking data exists. SHLP2 has not been studied in combination with any other compound in clinical or rigorous preclinical settings. Combinations described in online research-chemical communities are anecdotal and lack any evidentiary basis. Given CXCR7 agonist activity and hypothalamic POMC modulation, combinations with other neuropeptides or metabolic agents carry theoretical but uncharacterized interaction risks.

Legal & regulatory. Not FDA-approved. No Investigational New Drug (IND) application identified; no active clinical development program. SHLP2 is available commercially from research supply companies (e.g., Phoenix Pharmaceuticals, MedChemExpress, Isca Biochemicals) for in vitro and laboratory research use only. Not approved for human consumption. Not classified as a dietary supplement. The peptide sequence is covered by patent US8637470B2 and related USC-held patents. No federal scheduling or controlled-substance status; sold under standard research-chemical terms restricting human use.

Quality & harm reduction

Safer, legal alternative we recommend

Big Berb Energy. For a natural approach to the same metabolic/blood-sugar goal, our Berberine is a well-studied legal supplement.

See our recommended pick

Find SHLP2 (Small Humanin-Like Peptide 2) →

Know your numbers before you research

Order your own bloodwork online — hormone, metabolic and inflammation panels, no doctor visit needed. Know your baselines before and during any protocol. Independent bloodwork is the cheapest insurance there is.

Get tested with Ulta Lab Tests →

Frequently asked questions

What is SHLP2 and where does it come from?

SHLP2 is a 26-amino acid peptide encoded within mitochondrial DNA, specifically the MT-RNR2 (16S rRNA) gene. It is one of six Small Humanin-Like Peptides (SHLP1-6) discovered by researchers at USC. The body appears to produce it endogenously, though circulating levels and physiological regulation in humans are not well characterized.

Has SHLP2 been tested in humans?

No. As of mid-2025, no human clinical trials have been conducted or registered for SHLP2. All published research involves cell culture experiments and rodent models. Researchers in the primary literature explicitly state that IND-enabling preclinical toxicology work is needed before any human study could begin.

What are the most significant findings so far?

The two most developed findings are: (1) in AMD-patient-derived retinal cells, SHLP2 restored mitochondrial respiratory complex proteins and reduced cell death; and (2) in high-fat-diet mice, centrally administered SHLP2 activated hypothalamic POMC neurons, suppressed food intake, and improved insulin sensitivity. Both are preclinical findings that require human validation.

What is the appropriate dose of SHLP2?

No human dosing information exists. Rodent experimental doses described in the literature are not translatable to human use without pharmacokinetic bridging studies that have not been performed. This entry does not provide dosing guidance; anyone considering a peptide for a medical or health purpose should consult a licensed clinician.

Is SHLP2 legal to purchase in the United States?

SHLP2 is available from research supply companies for in vitro and laboratory research purposes and is not a federally scheduled substance. However, it is not approved for human consumption, not classified as a dietary supplement, and its sale for human use would be outside FDA approval. The peptide sequence is also patent-protected by USC.

Is there a safer, clinically validated alternative for SHLP2's proposed uses?

For metabolic health and obesity, GLP-1 receptor agonists (e.g., semaglutide) are FDA-approved with extensive human safety and efficacy data - an appropriate clinical option for eligible patients. For neuroprotection and mitochondrial support, no single approved drug replicates SHLP2's proposed mechanism, but disease-specific treatments exist for conditions like AMD and Parkinson's with established evidence bases. A clinician can advise on appropriate options for specific conditions.

References & further reading

PubMed: SHLP2 macular degeneration ARPE-19 cybrid OXPHOS (2018, Scientific Reports / PMC6182005)
PubMed: SHLP2 energy homeostasis hypothalamus POMC obesity insulin 2023 Nature Communications (s41467-023-40082-7)
PubMed: mitochondrial-derived peptide humanin SHLP chaperone amyloid 2017 Scientific Reports
PubMed: humanin SHLP6 natural selection mitochondrial peptide 2023 (PMC10465549)
Google Patents: US8637470B2 Small humanin-like peptides Cohen USC