Abstract & Overview
Ara‑290 is a synthetic 11‑amino‑acid peptide derived from the tertiary structure of erythropoietin (EPO), specifically the region associated with tissue‑protective signaling rather than hematopoiesis. It functions as a selective activator of the innate repair receptor (IRR), a heteroreceptor complex formed by the erythropoietin receptor (EPOR) and CD131 (β common receptor). By engaging this receptor pathway, Ara‑290 exerts potent anti‑inflammatory, anti‑apoptotic, and tissue‑protective effects without stimulating red blood cell production. This property has made Ara‑290 a leading research tool for studying cellular repair, immune modulation, and neuroprotection.
Molecular Pharmacology
Ara‑290 is composed of the amino acid sequence MQAWLTSPVDSAGPV, corresponding to the helix B surface region of the erythropoietin molecule. This truncated form eliminates the erythropoietic binding domain but preserves affinity for the EPOR/CD131 receptor complex. Its activity is mediated by transient and selective activation of the IRR, which promotes intracellular survival signaling cascades including JAK2/STAT3, PI3K/Akt, and NF‑κB modulation. Through these pathways, Ara‑290 supports mitochondrial integrity, reduces oxidative stress, and enhances cellular resilience under hypoxic or inflammatory conditions.
Mechanism of Action
Ara‑290’s mechanism centers on selective IRR activation, distinguishing it from full‑length EPO and recombinant analogs that stimulate erythropoiesis. Binding to the EPOR/CD131 heteroreceptor activates JAK2 phosphorylation, leading to downstream STAT3 and Akt signaling. This activation inhibits pro‑inflammatory cytokine release, suppresses apoptosis, and facilitates tissue remodeling. Additionally, Ara‑290 has been shown to enhance endothelial function, increase nitric oxide bioavailability, and promote vascular stabilization—key contributors to its regenerative and cytoprotective profile.
Tissue Protection and Regenerative Research
Extensive studies demonstrate Ara‑290’s ability to protect neural, cardiac, renal, and hepatic tissues from injury. In preclinical models of ischemia, Ara‑290 reduces infarct size, mitigates oxidative damage, and improves tissue perfusion. Its anti‑inflammatory signaling contributes to microvascular stability and attenuation of leukocyte adhesion. In cardiac and renal models, Ara‑290 prevents fibrosis by downregulating TGF‑β and preserving mitochondrial homeostasis. Collectively, these findings support its value as a model compound for studying cytoprotection and tissue regeneration through non‑hematopoietic EPO signaling pathways.
Neuropathy and Pain Signaling
One of the most promising research applications of Ara‑290 lies in neuropathic and neuroinflammatory conditions. In small fiber neuropathy models, Ara‑290 enhances peripheral nerve regeneration and reverses pain hypersensitivity by restoring axonal mitochondrial function. It also modulates microglial activation and inflammatory cytokine production in central and peripheral nervous tissue. Through these mechanisms, Ara‑290 serves as a model compound for understanding nerve repair, neuroimmune regulation, and pain transmission in chronic injury contexts.
Comparative Signaling: Ara‑290 vs. EPO and HBSP
Full‑length erythropoietin activates both homodimeric EPOR and the heteromeric EPOR/CD131 complex, resulting in erythropoiesis and tissue protection, respectively. In contrast, Ara‑290 exclusively targets the latter, thereby isolating the cytoprotective effects of EPO without hematologic stimulation. Helix‑B Surface Peptide (HBSP) shares structural homology and functional overlap with Ara‑290, but differs slightly in stability and receptor affinity. Both peptides are instrumental in defining the IRR pathway’s role in non‑hematopoietic EPO signaling, emphasizing receptor‑specific tissue protection as a research focus.
Summary
Ara‑290 represents a paradigm shift in the study of erythropoietin‑derived peptides by dissociating tissue‑protective signaling from erythropoiesis. Through selective activation of the EPOR/CD131 complex, it enables investigation into anti‑inflammatory, anti‑apoptotic, and regenerative processes across multiple organ systems. Its robust mechanistic foundation and reproducible effects in neural and microvascular models make Ara‑290 a key reference compound for exploring targeted peptide therapeutics and cellular resilience pathways.
Educational & Research Disclaimer
This article is for educational and scientific research purposes only. No therapeutic claims or usage recommendations are provided. Compounds referenced are not approved for human use and are intended solely for controlled laboratory experimentation.
Ara-290 is an 11–amino-acid peptide derived from erythropoietin (EPO), designed to activate tissue-protective signaling pathways without stimulating red blood cell production.
Ara-290 selectively activates the innate repair receptor (IRR), a receptor complex involving EPOR and CD131, which is associated with anti-inflammatory, anti-apoptotic, and cellular protection signaling.
No. Unlike full-length erythropoietin, Ara-290 does not stimulate erythropoiesis or increase red blood cell production.
Ara-290 has been studied in models of neuropathic pain, tissue injury, inflammation, and neuroimmune signaling due to its cytoprotective and reparative properties.
Preclinical and clinical research suggests Ara-290 supports neuroprotective and neuroimmune modulation pathways, particularly in peripheral neuropathy models.
No. Ara-290 is a small peptide fragment engineered to retain tissue-protective signaling while eliminating erythropoietic activity.
PMID: 16888043 – Brines M, Cerami A. Discovery of erythropoietin’s tissue-protective and non-hematopoietic biological functions.
PMID: 17644734 – Identification of the erythropoietin–CD131 heteroreceptor responsible for tissue protection without erythropoiesis.
PMID: 20172558 – Evaluation of Ara-290 as a non-erythropoietic erythropoietin analog in neuropathic pain models.
PMID: 22954607 – Characterization of Ara-290 as a novel erythropoietin-derived peptide with cytoprotective and anti-inflammatory properties.
PMID: 23878234 – Clinical investigation of Ara-290 in small fiber neuropathy associated with sarcoidosis.
PMID: 24316313 – Review of receptor mechanisms mediating erythropoietin’s tissue-protective signaling pathways.
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