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Apelin

Apelin is an endogenous peptide hormone that functions as one of the primary ligands for the apelin receptor (APJR), a class A G protein-coupled receptor (GPCR) widely expressed in the cardiovascular system, central nervous system, and other tissues.^[1] Discovered in 1998 through screening of bovine stomach extracts for ligands of orphan GPCRs, apelin was subsequently detected in bovine colostrum and human plasma, marking it as a key regulator of physiological homeostasis.^[2] Derived from a 77-amino-acid preproapelin precursor, apelin exists in multiple bioactive isoforms, including apelin-13, apelin-17, and apelin-36, all sharing a conserved C-terminal RPRL motif essential for receptor binding and activation.^[1] The apelinergic system, comprising apelin and its receptor, exerts diverse effects through G-protein-mediated signaling pathways such as ERK, PI3K/Akt, and p70S6 kinase, as well as β-arrestin-dependent mechanisms, enabling biased agonism that fine-tunes cellular responses.^[1] In the cardiovascular system, apelin promotes vasodilation, enhances cardiac contractility, and lowers blood pressure via nitric oxide production, while counteracting fluid overload in conditions like heart failure by inhibiting vasopressin release.^[3] It also plays a protective role in cardiac hypertrophy and development, influencing angiogenesis and myocardial function during embryogenesis.^[1] Beyond the heart and vessels, apelin regulates metabolic homeostasis by improving insulin sensitivity, glucose tolerance, and energy expenditure, with implications for obesity, diabetes, and insulin resistance.^[4] In the reproductive system, it modulates gonadotropin release, ovarian function, and sperm motility across species, highlighting its endocrine versatility.^[5] Additionally, apelin contributes to fluid balance by antagonizing vasopressin's antidiuretic effects in the kidney, positioning it as a counter-regulatory peptide in water homeostasis.^[3] Emerging research underscores its therapeutic potential in cardiovascular diseases, metabolic disorders, and even cancer, where it exhibits context-dependent effects on tumor progression and angiogenesis.^[1]

Molecular Aspects

Discovery

Apelin was first discovered in 1998 by a team led by Masahiko Fujino at Gunma University and Takeda Pharmaceutical Company, who isolated it from bovine stomach extracts as a novel bioactive peptide serving as an endogenous ligand for the orphan G-protein-coupled receptor APJ. The researchers identified apelin through a screening process targeting peptides that bound to APJ, revealing a 36-amino-acid peptide (apelin-36) as the predominant form in bovine tissue, with shorter processed variants also detected. Concomitant with its isolation, the APLN gene encoding the apelin preproprotein was identified through cDNA cloning efforts, allowing deduction of the full bovine and human preproapelin sequences. These early cloning studies established that the human APLN gene is located on the X chromosome and encodes a 77-amino-acid prepropeptide, providing the foundational molecular framework for subsequent research on apelin. The APLN nomenclature was later adopted to reflect its genetic basis, distinguishing it from the receptor.^[6] Key early studies conducted before 2000 further characterized apelin's distribution across various tissues, including high levels in the stomach, brain, and other organs, and confirmed its high-affinity binding to the APJ receptor, which shares structural similarity with angiotensin receptors but lacks responsiveness to known ligands at the time. These investigations laid the groundwork for understanding apelin as a bioactive peptide with potential regulatory roles, though functional details emerged later. In 2013, Elabela (also known as Toddler or ELA) was identified as a second endogenous ligand for the APJ receptor through genomic and functional screens in zebrafish embryos, where it was found to be essential for cardiac morphogenesis and early heart development. This discovery highlighted a dual-ligand system for APJ, with Elabela exhibiting distinct expression patterns during embryogenesis compared to apelin, and it was shown to activate similar signaling pathways while being indispensable for endocardial differentiation in zebrafish.

Biosynthesis and Structure

Apelin is encoded by the human APLN gene, located on the X chromosome at locus Xq25-26.1, which consists of three exons and produces a 77-amino acid precursor protein known as pre-proapelin.^[6]^[7] This pre-proapelin undergoes post-translational processing, primarily through enzymatic cleavage by prohormone convertases and carboxypeptidases, to generate several bioactive C-terminal fragments. The full mature form is apelin-36, which can be further truncated to apelin-17 and apelin-13; the latter is considered the most potent isoform due to its high affinity for the receptor. Additionally, apelin-13 can cyclize at its N-terminus to form the pyroglutamated variant [Pyr¹]apelin-13, enhancing its stability against degradation.^[8]^[9] The structural features of apelin peptides are critical for their biological activity, with the C-terminal region being essential for receptor binding and activation. In apelin-13, the conserved RPRL motif at the C-terminus (positions 10-13: Arg-Pro-Arg-Leu) plays a key role in high-affinity interactions, as amino acid substitutions in this motif abolish binding. Mass spectrometry analysis has identified 46 distinct endogenous apelin-related peptides in bovine colostrum, ranging from the full pro-form to various truncated isoforms, highlighting the diversity of processing in biological fluids.^[1]^[10]^[11] APLN mRNA exhibits tissue-specific expression patterns, with particularly high levels in the heart, brain, and kidney, as well as moderate expression in adipose tissue, lung, and gastrointestinal tract. This distribution underscores apelin's role in multiple physiological systems, where the processed peptides bind to the APJ receptor to exert effects.^[7]^[12]

Receptor and Signaling

APJ Receptor

The apelin receptor, also known as APJ, is a G protein-coupled receptor (GPCR) belonging to the class A (rhodopsin-like) subfamily, encoded by the APLNR gene located on human chromosome 11q12.^[13] This gene produces a 380-amino-acid protein that shares structural homology with other peptide-binding GPCRs, such as the angiotensin II type 1 receptor, though with only about 40% sequence identity.^[14] Like typical class A GPCRs, APJ features seven transmembrane α-helices connected by three intracellular and three extracellular loops, with an extracellular N-terminal domain that contributes to ligand recognition.^[15] Structural insights into APJ were advanced by the 2.6 Å-resolution crystal structure determined in 2017, which revealed the receptor's inactive conformation bound to a designed apelin mimetic peptide agonist.^[16] This structure highlighted a deep binding pocket within the transmembrane bundle, primarily formed by residues in helices 2, 3, 6, and 7, where the C-terminal portion of apelin engages key interactions, including hydrogen bonds and hydrophobic contacts essential for high-affinity binding. Subsequent cryo-EM studies have further elucidated the active-state conformation with apelin-13, confirming the pocket's role in stabilizing the receptor upon ligand engagement.^[17] APJ exhibits a broad tissue distribution, with high expression levels in the heart (particularly endothelial and smooth muscle cells), vasculature, brain (including hypothalamus and cortex), kidney (glomeruli and tubules), and adipose tissue.^[18] This pattern underscores its roles in multiple organ systems, and the receptor's sequence is highly conserved evolutionarily, with orthologs identified in vertebrates ranging from zebrafish to mammals, reflecting over 90% identity in core transmembrane regions across mammalian species.^[19] In terms of ligand specificity, APJ binds its endogenous peptides apelin and Elabela (also known as Toddler) with high affinity, while showing no significant interaction with other known peptide ligands such as angiotensin II.^[16] For instance, apelin-13 exhibits a dissociation constant (Kd) of approximately 1-2 nM, enabling potent activation at physiological concentrations.^[20]

Signaling Pathways

Upon binding to its cognate receptor APJ, a G protein-coupled receptor with seven transmembrane domains, apelin primarily engages Gi/o proteins to initiate intracellular signaling. This coupling inhibits adenylate cyclase activity, thereby reducing cyclic AMP (cAMP) levels and modulating downstream effectors in various cell types.^[21] Such Gi/o-mediated inhibition has been demonstrated in heterologous systems like CHO cells expressing APJ, where apelin-13 potently suppresses forskolin-stimulated cAMP accumulation with an IC50 in the nanomolar range.^[22] In addition to G protein-dependent pathways, apelin induces β-arrestin recruitment to APJ, facilitating biased agonism that diverges from classical Gi/o signaling. This β-arrestin pathway activates mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and protein kinase C (PKC) cascades, often independently of cAMP modulation. For instance, apelin-13 stimulates ERK1/2 phosphorylation via Gi2 coupling in human APJ-expressing cells, while longer isoforms like apelin-17 promote β-arrestin-dependent ERK activation, highlighting ligand-specific bias.^[22] PI3K/Akt activation occurs through Gαi/Gαq interfaces, enhancing cell survival signals, whereas PKC is mobilized via phospholipase C hydrolysis following Gαq engagement.^[23] Biased signaling toward β-arrestin over Gi has been observed with C-terminally truncated apelin fragments, which retain Gi potency but show reduced β-arrestin efficacy, underscoring the therapeutic potential of pathway-selective agonists.^[24] Apelin-APJ signaling further promotes nitric oxide (NO) production in endothelial cells by phosphorylating endothelial nitric oxide synthase (eNOS) at serine 1177, primarily through the PI3K/Akt axis. This eNOS activation increases NO bioavailability, supporting vascular homeostasis.^[25] In cardiomyocytes, apelin elicits intracellular calcium mobilization, enhancing transient amplitudes despite reducing sarcoplasmic reticulum stores, via PKC and IP3-mediated release.^[26] Apelin signaling exhibits cross-talk with other systems, notably antagonizing angiotensin II type 1 (AT1) receptor effects through allosteric trans-inhibition and increased NO to counteract vasoconstriction and oxidative stress.^[27] Similarly, apelin opposes vasopressin V1a receptor-mediated actions by inhibiting AVP neuronal activity and release in hypothalamic magnocellular neurons, thereby promoting diuresis.^[28]

Physiological Functions

Vascular Effects

Apelin is expressed in endothelial cells of the vasculature, where it plays a critical role in embryonic vascular development. During early embryogenesis in model organisms such as mice and frogs, the APJ receptor, the cognate receptor for apelin, is highly expressed in endothelial precursor cells and nascent vascular structures, including those sprouting from the dorsal aorta. Apelin signaling is essential for normal vascular formation, as its disruption impairs endothelial cell differentiation and the establishment of a functional circulatory system.^[29]^[30] In mature vasculature, apelin exerts potent vasodilatory effects primarily through activation of endothelial cells, leading to the release of nitric oxide (NO) and subsequent relaxation of vascular smooth muscle. This process involves apelin binding to the APJ receptor, which couples to Gi proteins to stimulate endothelial nitric oxide synthase (eNOS) phosphorylation and NO production, as well as endothelium-dependent hyperpolarization via potassium channel activation. In animal models, such as rats and mice, systemic administration of apelin lowers mean arterial blood pressure in a dose-dependent manner, with effects abolished by eNOS inhibitors or endothelial denudation, confirming the endothelium-dependent nature of this vasodilation.^[25] Apelin also promotes angiogenesis by enhancing endothelial cell proliferation, migration, and tube formation, often in synergy with vascular endothelial growth factor (VEGF). In vitro studies demonstrate that apelin stimulates endothelial cell proliferation at concentrations comparable to VEGF, while in vivo, it induces VEGF expression in hypoxic conditions to support new vessel formation. These actions contribute to the expansion and remodeling of vascular networks during development and physiological adaptation.^[31]^[29] Apelin regulates vascular tone in response to hemodynamic stimuli, particularly shear stress, with the apelin-13 isoform exhibiting the highest potency among apelin peptides for these effects. Endothelial expression of apelin and APJ is upregulated by laminar shear stress, which enhances NO-mediated vasodilation and maintains vascular homeostasis. In human umbilical vein endothelial cells exposed to controlled flow, apelin-13 synergizes with shear stress to activate PI3K/Akt/eNOS signaling, optimizing vessel caliber and tone without direct effects on smooth muscle contraction under normal conditions.^[32]^[33]

Cardiac Effects

Apelin exerts positive inotropic effects on cardiomyocytes primarily through modulation of intracellular calcium handling. Activation of the APJ receptor by apelin enhances the amplitude of calcium transients in isolated rat ventricular myocytes, despite a reduction in sarcoplasmic reticulum calcium content, leading to increased sarcomere shortening and contractility without altering heart rate.^[34] This effect has been observed in both normal and failing cardiomyocytes, where apelin concentrations as low as 1 nM significantly boost shortening amplitude.^[35] In embryonic development, apelin is essential for heart morphogenesis, including the formation of cardiac valves. It promotes endocardial protrusions that contribute to atrioventricular cushion development, a critical step in valve formation, as demonstrated in zebrafish models where myocardial-derived apelin signaling drives this process.^[36] Apelin knockout mice exhibit normal gross heart morphology at birth but display impaired basal cardiac contractility, highlighting apelin's role in establishing functional heart development.^[37] These effects involve APJ-mediated activation of Akt and ERK pathways in cardiomyocytes.^[38] Apelin also regulates coronary blood flow and offers cardioprotection in healthy hearts. In human studies, intracoronary administration of apelin-36 increases coronary blood flow while enhancing left ventricular contractility.^[39] Furthermore, apelin pretreatment limits ischemia-reperfusion injury in isolated hearts by reducing infarct size and preserving postischemic function through anti-apoptotic mechanisms.^[40] Circulating apelin levels in healthy individuals are detectable in plasma, with apelin-like immunoreactivity present in both atrial and ventricular tissues.^[41] These levels rise in response to physiological stressors such as acute systemic hypoxia, increasing up to twofold in humans exposed to reduced oxygen conditions, which supports apelin's adaptive role in cardiac homeostasis.^[42]

Neurological Effects

Apelin and its receptor APJ are widely expressed in the mammalian brain, with notable localization in key regions involved in neuroendocrine regulation. In the hypothalamus, apelin immunoreactivity is prominent in the supraoptic nucleus (SON) and paraventricular nucleus (PVN), including both magnocellular and parvocellular subdivisions, where it colocalizes with vasopressin neurons.^[43] Expression extends to the pituitary gland, influencing hormone release, and to the brainstem, particularly the medulla oblongata, where APJ receptors are detected in neuronal populations.^[43] These distributions support apelin's roles in central nervous system homeostasis. A primary physiological function of apelin in the brain is the regulation of fluid homeostasis through antagonism of vasopressin (AVP) signaling. Central administration of apelin-17 inhibits phasic electrical activity in hypothalamic AVP neurons, reducing intraburst spike frequency and overall AVP release from the posterior pituitary by approximately 40%.^[44] This action promotes diuresis, increasing urine output without affecting electrolyte excretion, and counters AVP-induced water retention, thereby reducing water intake during conditions like dehydration to maintain osmotic balance.^[44] Under basal conditions, apelin exerts neuroprotective effects on neurons by activating anti-apoptotic pathways. In cortical neurons, apelin-13 prevents apoptosis induced by serum deprivation through the PI3K/Akt signaling cascade, which phosphorylates Akt to maintain mitochondrial integrity, reduce reactive oxygen species, and inhibit caspase-3 activation.^[45] This protection involves upregulation of the anti-apoptotic protein Bcl-2 and downregulation of pro-apoptotic Bax and caspase-3, preserving neuronal viability without external stressors.^[46] Apelin modulates pain perception via supraspinal mechanisms involving APJ receptors. Intracerebroventricular injection of apelin-13 produces dose-dependent antinociception in thermal pain models, peaking at 15 minutes post-administration and mediated primarily through APJ activation and subsequent engagement of μ-opioid receptors, as evidenced by reversal with APJ antagonists and naloxone.^[47] In the context of stress responses, apelin influences the hypothalamic-pituitary-adrenal (HPA) axis by stimulating corticotrophin-releasing factor (CRF) and AVP-dependent pathways in the PVN. Central apelin-13 administration elevates plasma ACTH by over 200% and corticosterone by nearly 190% of baseline levels, enhancing HPA activation to facilitate adaptive physiological responses to stressors.^[48]

Metabolic and Endocrine Effects

Apelin is secreted by adipocytes in response to insulin stimulation, which significantly increases its expression in mature adipocytes such as 3T3-L1 cells.^[49] This insulin-regulated secretion plays a key role in peripheral energy homeostasis by promoting glucose uptake in adipose tissue through activation of AMP-activated protein kinase (AMPK) in a dose-dependent manner.^[50] Concurrently, apelin inhibits lipolysis by phosphorylating hormone-sensitive lipase (HSL) via Gq, Gi, and AMPK-dependent mechanisms, while increasing perilipin content around lipid droplets to reduce free fatty acid release.^[4]^[8] Apelin also contributes to appetite regulation, exhibiting mixed effects depending on administration route and duration; central administration of apelin-13 suppresses food intake in mice via hypothalamic APJ receptor activation, potentially mediated by the corticotropin-releasing factor (CRF) pathway.^[51] In glucose metabolism, apelin enhances insulin secretion from pancreatic beta cells under basal conditions, supporting euglycemia in physiological states.^[52] Furthermore, apelin levels display circadian rhythm modulation, with plasma concentrations varying diurnally in normal mice, peaking at specific times to align with metabolic demands.^[53] This rhythmicity facilitates apelin's interplay with leptin, another adipokine derived from adipose tissue, in maintaining overall energy balance through coordinated regulation of feeding and expenditure.^[8]

Gastrointestinal Effects

Apelin is expressed in the gastric and intestinal mucosa, including epithelial cells and endocrine cells, where it contributes to the regulation of digestive processes. In the stomach, apelin localizes to parietal cells and enterochromaffin-like (ECL) cells, facilitating local paracrine signaling. Similarly, in the small intestine, apelin is found in enterocytes and submucosal glands, supporting mucosal homeostasis.^[54] Apelin inhibits gastric acid secretion by suppressing histamine release from ECL cells through activation of APJ receptors, establishing a negative feedback loop with parietal cells to modulate acid production during digestion. This inhibitory effect on ECL cell activity reduces intracellular calcium signaling in response to gastrin stimulation, thereby limiting histamine-mediated stimulation of parietal cells.^[55] In the pancreas, apelin modulates exocrine function by decreasing pancreatic blood flow and enzyme secretion, while in the endocrine compartment, it reduces postprandial insulin release from beta cells via phosphodiesterase 3B activation, helping to fine-tune glucose handling after meals.^[56]^[57] Apelin influences gut motility by promoting smooth muscle relaxation in the gastrointestinal tract, primarily through nitric oxide-mediated pathways that inhibit contractile activity. This relaxation contributes to delayed gastric emptying and reduced intestinal transit under physiological conditions.^[58] Additionally, apelin supports gastric mucosa integrity by enhancing microcirculation and reducing lipid peroxidation, thereby maintaining barrier function during normal digestive processes.^[59]

Skeletal and Bone Effects

Apelin promotes skeletal muscle hypertrophy by activating the mTOR pathway in myotubes, particularly in response to exercise stimuli. In differentiated myotubes, apelin treatment enhances protein synthesis through the PI3K/Akt/mTOR signaling axis, which serves as a central regulator of muscle growth and adaptation to physical activity.^[60] This mechanism is evident in high-intensity interval training models, where apelin deficiency impairs Akt phosphorylation and shifts muscle fiber composition toward slower types, reducing overall myofiber size and hypertrophic potential.^[60] Apelin is expressed in osteoblasts, where it supports bone formation by stimulating cell proliferation and promoting mineralization. Human osteoblasts constitutively produce apelin and its receptor APJ, and exogenous apelin-13 activates the APJ/PI3K/Akt pathway to drive proliferation without altering differentiation markers like alkaline phosphatase activity, osteocalcin, or type I collagen production.^[61] In bone marrow mesenchymal stem cells undergoing osteogenic differentiation, apelin enhances mineralization and upregulates key genes such as RUNX2, COL1A1, and OCN, partly through Wnt/β-catenin signaling, leading to increased mineral nodule formation.^[62] Skeletal muscle apelin levels decline with age, contributing to impaired mitochondrial function and reduced muscle maintenance. This age-associated reduction in apelin expression correlates with diminished mitochondrial biogenesis, as apelin normally upregulates PGC-1α to boost ATP production and coupling efficiency in myotubes.^[63] In aging muscle tissues, the loss of apelin signaling exacerbates mitochondrial dysfunction, highlighting its role in preserving energy metabolism during healthy aging.^[60] Physical activity induces apelin expression and release in skeletal muscle and elevates circulating levels in plasma, facilitating post-exercise recovery. Acute bouts of exercise, such as maximal treadmill running, transiently increase plasma apelin-13 and apelin-36 concentrations, with greater responses in trained individuals, supporting muscle metabolic adaptation and repair.^[64] Contracting myotubes secrete apelin, and in vivo exercise models show upregulated apelin in muscle tissue, which aids recovery by enhancing mitochondrial function and fiber type maintenance.^[60]

Pathophysiological Roles

Cardiovascular Diseases

In chronic heart failure (CHF), plasma apelin levels are often elevated and serve as a potential biomarker for disease progression and prognosis. Studies have shown that higher circulating apelin concentrations, such as levels exceeding 3.55 ng/mL, are associated with a more favorable clinical course in heart failure patients with type 2 diabetes, correlating with reduced hospitalization rates and improved survival outcomes.^[65] This elevation may reflect a compensatory response to cardiac stress, where apelin acts protectively against adverse ventricular remodeling. Specifically, apelin exerts anti-fibrotic effects by inhibiting transforming growth factor-β signaling and modulating matrix metalloproteinase activity, thereby reducing collagen deposition and myocardial stiffness in failing hearts.^[66] These mechanisms help mitigate the progression of fibrosis, a hallmark of CHF that contributes to systolic dysfunction.^[67] In pulmonary hypertension (PH), apelin levels are typically reduced, promoting pulmonary vasoconstriction and exacerbating right ventricular strain. Patients with pulmonary arterial hypertension (PAH) exhibit lower plasma apelin concentrations and decreased expression in pulmonary endothelial cells, which correlates with increased vascular resistance and disease severity.^[68] This deficiency impairs apelin's vasodilatory actions, leading to heightened hypoxic pulmonary vasoconstriction in preclinical models. Apelin deficiency also worsens atherosclerosis by enhancing oxidative stress and plaque instability in vascular walls. In apelin-null mice, accelerated atherosclerotic lesion formation occurs under hypercholesterolemic conditions, highlighting apelin's role in suppressing endothelial inflammation and lipid accumulation.^[27] Following myocardial infarction (MI), apelin plays a critical role in recovery by limiting infarct expansion and preventing the onset of heart failure when administered early. A 2024 study demonstrated that prompt apelin infusion post-MI in murine models improved left ventricular ejection fraction and reduced remodeling, averting transition to decompensated heart failure through enhanced cardiomyocyte survival and angiogenesis.^[69] Microparticle-mediated sustained release of apelin further amplified these benefits, decreasing scar size and preserving cardiac output in post-MI mice.^[66] Apelin interacts antagonistically with the renin-angiotensin-aldosterone system (RAAS), counteracting angiotensin II (Ang II)-induced cardiac hypertrophy in hypertensive models. Apelin signaling upregulates angiotensin-converting enzyme 2 (ACE2), which degrades Ang II to its protective metabolite angiotensin-(1-7), thereby attenuating hypertrophy and fibrosis in pressure-overloaded hearts.^[70] In apelin-deficient states, Ang II effects are amplified, leading to exacerbated left ventricular hypertrophy and diastolic dysfunction, underscoring apelin's counter-regulatory function within RAAS pathways.^[71]

Cancer

Apelin, through its receptor APJ, promotes tumor angiogenesis and metastasis in glioblastoma (GBM) and various other cancers by activating pathways that enhance vascularization and invasive behavior. In GBM, apelin signaling drives endothelial cell proliferation, migration, and tube formation, while also supporting glioblastoma stem-like cell (GSC) maintenance and invasion, as evidenced by studies showing that apelin-13 rescues angiogenesis in apelin-knockout models and that APJ inhibition reduces vascular density and tumor spread.^[72]^[73] Similar mechanisms operate in solid tumors, where apelin/APJ activation fosters neovascularization essential for tumor sustenance and metastatic dissemination.^[74] In the tumor microenvironment, apelin is upregulated, particularly in hypoxic regions and endothelial cells, where it stimulates endothelial proliferation and contributes to immune evasion by inducing endothelial anergy, thereby limiting immune cell infiltration and supporting tumor progression. This upregulation has been observed in cancers such as non-small cell lung cancer and ovarian cancer, where elevated apelin correlates with increased vascular permeability and reduced antitumor immunity.^[74]^[72] Apelin exhibits a dual role in oncogenesis, acting predominantly as pro-tumorigenic in most solid tumors—such as breast and colon cancers, where it enhances cell migration, invasion, and STAT3-mediated metastasis—but showing potential anti-tumor effects in certain leukemias by altering immune cell localization and suppressing aberrant proliferation.^[74] High apelin expression consistently correlates with poor prognosis across these solid tumors, including reduced overall survival in ovarian and breast cancers.^[74] Recent studies indicate that apelin inhibition markedly reduces tumor invasiveness and growth; for instance, antagonists like ML221 and MM54 have decreased metastatic potential in cholangiocarcinoma and GBM models, respectively, by impairing APJ-mediated signaling and enhancing therapeutic sensitivity. In a 2025 investigation, apelin blockade suppressed colorectal liver metastasis in preclinical settings, highlighting its promise as an oncology target.^[74]^[75]^[73]

Neurological Disorders

Apelin has emerged as a key modulator in neurological disorders, particularly through its interaction with the APJ receptor, offering neuroprotective effects in various pathological conditions. In ischemic stroke, apelin-13 administration significantly reduces oxidative stress by decreasing reactive oxygen species (ROS) levels and enhancing antioxidant protein expression, thereby conferring neuroprotection.^[76] This mechanism involves the apelin/APJ axis, which mitigates cerebral ischemic injury and has been highlighted in recent reviews as a promising therapeutic target.^[76] Furthermore, apelin-13 treatment in experimental models of ischemic stroke decreases infarct size, alleviates brain edema, and improves neurological outcomes by activating the APJ receptor and suppressing inflammatory responses.^[77] In Alzheimer's disease (AD), dysregulation of apelin signaling contributes to disease progression, with significantly lower plasma levels of apelin-17 observed in patients compared to healthy controls, correlating with neurodegeneration and cognitive decline.^[78] Decreased apelin levels exacerbate amyloid-beta (Aβ) toxicity, as apelin-13 has been shown to suppress Aβ-induced neuroinflammation and amyloidogenesis in AD models, thereby ameliorating cognitive deficits and cholinergic dysfunction.^[79] Regarding tau pathology, apelin inhibits the phosphorylation and accumulation of tau protein, potentially reducing neurofibrillary tangle formation; apelin-13 analogs and related peptides demonstrate similar protective effects by enhancing synaptic plasticity and countering excitatory neuronal toxicity.^[80] These findings position the apelin/APJ system as a target for mitigating core AD pathologies. Apelin also plays a protective role in Parkinson's disease (PD) by preserving dopaminergic neurons. Activation of the APJ receptor by apelin-13 prevents degeneration in models of PD induced by toxins like rotenone, promoting autophagy through the AMPK/mTOR/ULK-1 pathway and reducing endoplasmic reticulum stress.^[81] In MPTP-induced PD mouse models, apelin reverses the loss of dopaminergic neurons in the substantia nigra, improves motor function, and attenuates α-synuclein accumulation by inhibiting related signaling pathways.^[82] These neuroprotective effects extend to broader regulation of neurotrophic factors and oxidative stress, underscoring apelin's potential in slowing PD progression.^[83] In epilepsy, the apelin/APJ system modulates seizure activity and offers anticonvulsant properties. Apelin-13 exhibits neuroprotective and antiseizure effects in pentylenetetrazol (PTZ)-induced seizure models by reducing seizure severity, neuronal damage, and oxidative stress in the hippocampus.^[84] Activation of APJ suppresses susceptibility to seizures, as demonstrated in PTZ models where APJ inhibition exacerbates epileptiform activity, while apelin modulates NMDA receptor endocytosis, particularly the GluN2B subunit, to dampen excitotoxicity.^[85] Although direct links to GABAergic enhancement remain under investigation, apelin's overall inhibition of hypersynchronous neuronal discharges highlights its therapeutic promise in epilepsy management.^[86]

Metabolic Disorders

In type 2 diabetes mellitus (T2DM), circulating apelin levels are significantly decreased compared to healthy controls, correlating negatively with fasting glucose (r = −0.272, P = .004) and HbA1c (r = −0.280, P = .003).^[87] This reduction impairs insulin sensitivity by diminishing glucose utilization and adipogenesis in insulin-resistant states.^[87] Restoration of apelin through targeted delivery, such as apelin-loaded small extracellular vesicles derived from mesenchymal stem cells, enhances insulin sensitivity in T2DM models by increasing Akt and AMPK phosphorylation, upregulating GLUT4 expression, and improving glucose uptake, thereby reducing plasma glucose levels and enhancing glycemic control. In obesity, apelin levels are elevated in serum and adipose tissue expression, serving as a compensatory mechanism in insulin-resistant states.^[88] However, this elevation is dysfunctional, as heightened apelin expression in adipose tissue contributes to local inflammation, exacerbating insulin resistance and chronic inflammatory processes. Apelin's role intersects with normal insulin modulation by promoting glucose uptake in adipose and muscle tissues, though this is detailed further in endocrine contexts.^[88] Apelin exerts protective effects in non-alcoholic fatty liver disease (NAFLD) by reducing hepatic steatosis through activation of the AMPK pathway and subsequent PPARα signaling, which enhances fatty acid oxidation and inhibits lipid accumulation in hepatocytes. This mechanism mitigates diet-induced liver fat buildup in both human and mouse models, positioning apelin as a potential therapeutic target for NAFLD progression. Apelin interacts with exercise in metabolic regulation, where acute and chronic physical activity typically elevates circulating apelin to support glucose homeostasis and energy metabolism.^[89] However, in metabolic syndrome, the apelin response to exercise is often blunted or inconsistent, with some interventions showing no significant increase or even reductions in apelin levels, potentially limiting the anti-inflammatory and insulin-sensitizing benefits of training.^[90]

Therapeutic Applications

Preclinical Studies

Preclinical studies on apelin modulation have primarily utilized animal models and in vitro systems to evaluate therapeutic potential across various diseases, focusing on agonists and antagonists to enhance or inhibit apelin/APJ signaling. These investigations have demonstrated promising outcomes in modulating cardiac function, tumor progression, metabolic homeostasis, and neuroprotection, laying the groundwork for translational applications.^[91] In rodent models of heart failure, apelin agonists such as [Pyr¹]apelin-13 have shown significant cardioprotective effects. Infusions of [Pyr¹]apelin-13 in chronic heart failure models increased cardiac index by approximately 10%, improved ejection fraction, and reduced systemic vascular resistance and blood pressure.^[92] Post-infarct administration in rat myocardial infarction models reduced myocardial damage through decreased oxidative injury and enhanced nitric oxide production, leading to improved cardiac function and reduced fibrosis.^[93] Similarly, chronic treatment with apelin analogs in pressure-overload mouse models prevented hypertrophy and fibrosis while enhancing contractility.^[94] A metabolically stable apelin-17 analog, LIT01-196, administered chronically post-myocardial infarction in rodent models, improved left ventricular function without decreasing blood pressure, increased cardiac vascular density, and reduced remodeling.^[95] Apelin receptor antagonists have exhibited anti-tumor efficacy in xenograft models of cancer, particularly glioblastoma (GBM). The selective antagonist MM54, administered at 2 mg/kg, reduced tumor expansion and vascularization in orthotopic GBM mouse models, extending survival without adverse effects on cardiac function or organ pathology.^[96] In subcutaneous GBM xenografts, MM54 inhibited tumor growth and metastasis by counteracting apelin-induced pro-tumorigenic effects from endothelial cells.^[97] These findings, corroborated in 2024 analyses, highlight antagonists' role in suppressing angiogenesis and invasion in aggressive cancers like GBM.^[97] Metabolically stable apelin analogs have demonstrated antidiabetic benefits in obese rodent models and cell lines. In diet-induced obese and db/db diabetic mice, chronic administration of analogs like (pGlu)apelin-13 amide improved glycemic control, enhanced insulin secretion during glucose tolerance tests, and reduced triglyceride levels by up to 34%, outperforming some incretin therapies.^[98] These analogs promoted glucose uptake in skeletal muscle and adipose tissue via AMPK and Akt pathways in insulin-resistant mice, without altering body weight or food intake.^[91] In vitro studies with human adipocytes and myotubes confirmed enhanced glucose utilization, supporting their potential in type 2 diabetes management, as reviewed in recent preclinical syntheses.^[99] Neuroprotective effects of apelin-13 have been evident in rat models of ischemic stroke from 2023 to 2025 studies. In middle cerebral artery occlusion (MCAO) models, apelin-13 treatment significantly reduced infarct volume (Hedges' g = 2.72) and neurological deficits (Hedges' g = 1.76), while decreasing apoptotic cell death via lowered cleaved caspase-3 levels (Hedges' g = 2.16).^[100] Intravenous administration preserved blood-brain barrier integrity, suppressed neuroinflammation, and enhanced functional recovery by inhibiting neuronal apoptosis and oxidative stress. Meta-analyses of these rodent data underscore apelin-13's consistent reduction in neuronal death and brain edema across multiple cohorts.^[100] A biased APJ agonist, MM07, has shown efficacy in preclinical models of pulmonary arterial hypertension, reversing structural and hemodynamic changes in the rat monocrotaline model comparably to macitentan.^[101]

Clinical Trials and Future Directions

A Phase 1b clinical trial of BGE-105 (azelaprag), an oral apelin receptor agonist, conducted in 2022 demonstrated its potential to mitigate muscle loss in older adults. In this study involving 21 healthy volunteers aged 65 years or older subjected to 10 days of strict bed rest, BGE-105 treatment resulted in statistically significant preservation of muscle mass compared to placebo, including 100% improvement in thigh circumference (p < 0.001), 58% improvement in vastus lateralis cross-sectional area (p < 0.05), and reduced deterioration in muscle quality as measured by Goutallier grade (p < 0.005).^[102] The drug was well-tolerated with no serious adverse events reported, consistent with safety profiles from prior Phase 1 studies in over 190 participants.^[102] However, a subsequent Phase 2 trial (STRIDES) evaluating BGE-105 alone and in combination with tirzepatide for obesity was discontinued in December 2024 after observing elevated liver transaminases in 11 of 204 participants, without associated clinical symptoms. A related trial in older adults with obesity was also terminated for the same reason. As of November 2025, BioAge Labs has reduced R&D expenses for the program and plans remain under evaluation following data analysis. In cardiovascular disease, recent data from apelin infusion studies in heart failure patients have highlighted improvements in hemodynamics. Intravenous apelin administration in these patients has been shown to increase cardiac output and left ventricular ejection fraction while reducing vascular resistance, with dose-dependent enhancements in cardiac function observed in clinical evaluations post-2023.^[103] These findings build on earlier infusion trials and underscore ongoing interest in apelin-based interventions for acute hemodynamic support in heart failure.^[104] Additionally, a Phase 1 trial (NCT06277336) evaluating intravenous [Pyr¹]apelin-13 in healthy volunteers with artificially induced syndrome of inappropriate antidiuresis (SIAD) was completed as of 2025, though results have not yet been posted.^[105] Early-phase exploratory studies on APJ antagonists for glioblastoma, reported in 2025, indicate potential anti-tumor effects by targeting the apelin/APJ pathway, which promotes vascularization, invasiveness, and therapy resistance in high-grade gliomas. Preclinical blockade of APJ in glioblastoma models reduced tumor growth and disrupted stem-like cell maintenance, suggesting a dual role in inhibiting angiogenesis and invasion, though human trials remain in nascent stages.^[72] Future directions in apelin therapeutics emphasize the development of biased agonists to enhance specificity and efficacy, particularly for neuroprotection. G-protein-biased APJ agonists, such as WN561 and MM07, are being explored to activate cardioprotective pathways while minimizing β-arrestin-mediated side effects like cardiac hypertrophy, with potential extensions to neuroprotective applications in stroke by reducing oxidative stress and neuronal apoptosis.^[106]^[76] BioAge Labs filed a provisional patent in May 2025 for a new class of orally active APJ agonists and entered an option agreement in June 2025 for a long-acting nanobody APJ agonist from JiKang Therapeutics. Preclinical data on PSTC1201, another oral APJ agonist, presented in June 2025, showed enhanced weight loss with muscle preservation when combined with semaglutide in diet-induced obese mice.^[107]^[108] However, key challenges include improving oral bioavailability—limited by apelin peptides' short half-life and non-compliance with Lipinski's rules for absorption—and achieving greater receptor specificity to avoid off-target effects in multi-disease contexts.^[109]^[110] Recent structural insights into APJ signaling support precision drug design, including allosteric modulators and bivalent ligands, to address these hurdles in 2024-2025 research agendas.^[106]

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