Neuropeptides最新文献

{"title":"The phoenixin-14/GPR173 Axis enhances post-stroke angiogenesis through ETS1-mediated VEGF signaling","authors":"Fangjie Luo ,&nbsp;Xiaoyun Li ,&nbsp;Guodao Wen ,&nbsp;Zhanpeng Zhu ,&nbsp;Junxi Lu ,&nbsp;Yuhao Weng","doi":"10.1016/j.npep.2026.102594","DOIUrl":"10.1016/j.npep.2026.102594","url":null,"abstract":"<div><div>Intracerebral hemorrhage (ICH) contributes to poor neurological outcomes by interfering with angiogenesis and disrupting important signaling pathways. Through ETS1-mediated vascular endothelial growth factor (VEGF) signaling, this work examines how the phoenixin-14/GPR173 axis promotes post-stroke angiogenesis. According to Western blot analysis, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay, blood phoenixin-14 levels and cortical GPR173 expression were considerably lower in a mouse ICH model than in sham controls. In addition to increasing serum VEGF-A and VEGF receptor-2 expression, administering two doses of phoenixin-14 (5 nmol and 10 nmol) improved neurological function, decreased cerebral edema, and raised cortical microvessel density in a dose-dependent manner. Hemin-treated human brain microvascular endothelial cells showed reduced levels of phoenixin-14 and GPR173 in vitro, while phoenixin-14 treatment increased the expression of VEGF-A and VEGF receptor-2, restored cell viability, and encouraged tube formation. Phoenixin-14 also elevated the phosphorylation of a transcription factor called ETS1, and its mechanistic function was confirmed when ETS1 knockdown eliminated the angiogenic and VEGF-inducing effects of phoenixin-14. These results show that via ETS1-mediated VEGF signaling, the phoenixin-14/GPR173 axis promotes post-stroke angiogenesis, indicating a possible therapeutic target for ICH recovery.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"117 ","pages":"Article 102594"},"PeriodicalIF":2.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147321923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Somatostatin neurons of the bed nucleus of the stria terminalis drive aversive behaviors in mice","authors":"Quentin Denis,&nbsp;Konstanze Krimbacher,&nbsp;Harish Iyer,&nbsp;Elisabeth Gasser,&nbsp;Anneliese Bukovac,&nbsp;Karma Moser,&nbsp;Heide Hörtnagl,&nbsp;Ramon Tasan","doi":"10.1016/j.npep.2026.102607","DOIUrl":"10.1016/j.npep.2026.102607","url":null,"abstract":"<div><div>Appropriate valence processing, a mechanism believed to assign emotional value to salient stimuli, is a pivotal element of responsive behavior. Malfunctioning of valence processing may compromise behavioral adaptation and facilitate the formation of disordered mental states. The bed nucleus of the stria terminalis (BNST), an essential part of the extended amygdala, has emerged as a sexually dimorphic forebrain area regulating positive and negative emotions. However, due to its structural and functional complexity, the contribution of individual BNST subpopulations remains elusive. Here, we investigated the role of somatostatin (SST)-expressing BNST neurons in valence processing and salience detection. We found that aversive challenges activate GABAergic BNST neurons, particularly those in the oval BNST co-expressing SST, but not coexisting glutamatergic BNST neurons. Interestingly, only the exogenous activation of SST GABA neurons resulted in conditioned place aversion both in male and female mice, while overall activation of BNST-GABA neurons did not promote aversive behavior. This indicates that especially BNST-SST neurons serve as essential detectors of salient stimuli initiating the generation of adaptive behavioral responses and significantly contribute to negative valence processing. Neuropeptide-expressing forebrain circuities may thus crystalize as an essential substrate for the maintenance of emotional-affective homeostasis.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"117 ","pages":"Article 102607"},"PeriodicalIF":2.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147388093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisited case for intranasal neuropeptide Y based therapeutics: From preclinical to clinical","authors":"Esther Louise Sabban ,&nbsp;Arax Tanelian","doi":"10.1016/j.npep.2026.102605","DOIUrl":"10.1016/j.npep.2026.102605","url":null,"abstract":"<div><div>Compelling evidence from a variety of approaches attributes manifold benefits to NPY in the brain. NPY can reduce stress, depressive symptoms, pain, neuroinflammation, seizures, and is implicated in attenuating alcohol use disorder and neurodegenerative diseases, such as Alzheimer's, Machado-Joseph and Huntington Disease. NPY enhances immune regulation, neuro-proliferation, memory and cognition. However, its therapeutic potential has not yet been realized. Intranasal nose to brain (N2B) delivery is a non-invasive approach that can provide high bioavailability with limited side effects. Here we discuss therapeutic opportunities and challenges of N2B administration of NPY and related agonists. Preclinical N2B administration of NPY, either alone or with other compounds, to experimental animals has been very successful. For example, a single NPY intranasal infusion to male rats was able to prevent, as well as reverse, many behavioral impairments triggered by Single Prolonged Stress model for PTSD. Females were found to require higher doses of NPY, or pretreatment with a DPPIV inhibitor, to provide resilience. In humans, limited studies found that intranasal administration of NPY in saline was well tolerated and showed promise for PTSD or depression at highest dose administered. However, saline should be avoided in favor of water for aqueous delivery, and each sex should be analyzed separately. Overall, these findings call for further work to enhance N2B delivery of NPY or selective agonists to human brain to harness NPY's exciting therapeutic potential.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"117 ","pages":"Article 102605"},"PeriodicalIF":2.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147388092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Netrin-3 rectifies diabetes-induced cognitive impairment by counteracting hippocampal oxidative stress and NLRP3 inflammasome activation","authors":"Yanhong Wang ,&nbsp;Mengmeng Pu ,&nbsp;Xuexue Wang","doi":"10.1016/j.npep.2026.102596","DOIUrl":"10.1016/j.npep.2026.102596","url":null,"abstract":"<div><div>Diabetes frequently causes substantial cognitive decline, yet available treatments offer minimal benefit. Netrin-3, a laminin-like protein, regulates nervous system development and inflammatory responses. However, its involvement in diabetes-associated cognitive impairment remains poorly understood. The escalating global diabetes burden, combined with the absence of disease-modifying therapies for cognitive complications, creates an urgent need to identify novel molecular targets. Our research evaluated whether Netrin-3 could counter cognitive deterioration using db/db mice as a type 2 diabetes model. We employed adenovirus-mediated gene delivery to restore Netrin-3 expression, then assessed spatial learning and memory using Morris water maze and Y-maze paradigms. Hippocampal tissue was analyzed by Western blot, quantitative PCR, ELISA, and oxidative stress assays to examine NF-κB/NLRP3 signaling and antioxidant enzyme activity. Initial analysis showed a considerable decrease in Netrin-3 expression within the cortex of diabetic mice. Introducing Netrin-3 via an adenoviral vector resulted in substantial improvements in systemic glucose control and insulin levels. Behavioral assessments further revealed that Netrin-3 reversed cognitive deficits, evidenced by superior performance in both Morris water maze and Y-maze paradigms, confirming enhanced spatial learning and working memory. At the mechanistic level, Netrin-3 counteracted hippocampal oxidative damage through lowering reactive oxygen species and NOX-4 expression, in parallel with reviving SOD and GSH-PX antioxidant enzyme function. Additionally, it curtailed the induction of the pro-inflammatory mediators IL-1β and IL-18 and blocked the triggering of the NF-κB/NLRP3 cascade. These findings indicate that Netrin-3 lessens cognitive dysfunction in diabetes by reducing oxidative damage and brain inflammation, highlighting its novel potential as a therapeutic target for a condition with limited treatment options.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"117 ","pages":"Article 102596"},"PeriodicalIF":2.7,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147321916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the brain through the nose: Advances in polymeric nanoparticle delivery for schizophrenia","authors":"Teja Kumar Ponduri ,&nbsp;G.S.N. Koteswara Rao","doi":"10.1016/j.npep.2026.102585","DOIUrl":"10.1016/j.npep.2026.102585","url":null,"abstract":"<div><div>Intranasal delivery of polymeric nanoparticles (PNPs) offers a promising approach for improving drug delivery to the central nervous system (CNS), particularly for treating schizophrenia. This delivery method enables direct nose-to-brain transport via olfactory and trigeminal pathways, bypassing the blood-brain barrier (BBB) and increasing therapeutic agent bioavailability in brain tissue while reducing systemic exposure and adverse effects. PNPs fabricated from natural polymers (chitosan, alginate, gelatin) and synthetic polymers (PLGA, polycaprolactone) provide controlled and sustained drug release, enhanced stability, and prolonged nasal residence time. Surface modifications with targeting ligands such as transferrin and lactoferrin have demonstrated 3.2 to 5.8 fold increases in brain accumulation compared to non-functionalized systems. Coating agents including polysorbate 80 and PEG further enhance nanoparticle transport efficiency and stability, with documented improvements of up to 10.86-fold in brain uptake. Beyond traditional antipsychotics, these nanocarrier platforms show significant potential for delivering neuropeptides (oxytocin, vasopressin) that address negative symptoms and cognitive deficits in schizophrenia. Novel nanoparticle-based delivery systems, including dendrimers, nanoemulsions, and lipid-based carriers, complement polymeric approaches to overcome limitations of conventional drug therapies. Despite robust preclinical efficacy data, clinical translation faces substantial challenges including interspecies anatomical differences (human olfactory epithelium represents only 3–5% of nasal surface area versus 50% in rodents), limited nasal cavity dose capacity, device-dependent delivery variability, absence of standardized assessment protocols, and insufficient long-term safety data for chronic administration. Future research must prioritize nanoparticle design optimization for enhanced mucoadhesion and mucopenetration, improved brain targeting through ligand engineering, validation in physiologically relevant models including ex vivo human tissue, comprehensive chronic toxicity evaluation, and alignment with evolving regulatory frameworks. Intranasal PNPs represent a paradigm shift in treating schizophrenia and other neuropsychiatric disorders, offering a non-invasive, patient-friendly, and potentially more effective therapeutic modality.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"116 ","pages":"Article 102585"},"PeriodicalIF":2.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of galanin/GALR2 signaling in the link between type 2 diabetes and Alzheimer's disease","authors":"Mengfan Xu ,&nbsp;Jia Wang ,&nbsp;Yuqing She ,&nbsp;Junbo He ,&nbsp;Mei Yu ,&nbsp;Zhenwen Zhang ,&nbsp;Penghua Fang","doi":"10.1016/j.npep.2026.102586","DOIUrl":"10.1016/j.npep.2026.102586","url":null,"abstract":"<div><div>Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) are two major healthcare problems among the elderly worldwide. Several epidemiological studies suggest that T2DM is associated with an increased risk of developing AD, leading to cognitive decline and loss of behavioral abilities. Despite many studies probing into the insulin resistance that serves as a pivotal etiopathology link between T2DM and AD, the precise mechanism for this association of both diseases is still poorly understood. Emerging evidence suggests that galanin and galanin receptor 2 (GALR2) are broadly described in the early steps of T2DM and AD and play the crucial role in the intersection between both two diseases in preclinical models. The dysregulation of the galanin-GALR2 axis plays a major role in the development of both diseases based on animal and cellular studies and has emerged as a plausible molecular pathogenesis link between them. In this review article, we mainly summarize our and other recent studies to provide a new insight into the multivariate relationship among galanin-GALR2, T2DM and AD, highlighting the beneficial effect of galanin/GALR2 signaling on the comorbid state of both diseases in preclinical models, and explain the underlying molecular mechanism in T2DM and AD pathogenesis. These may strengthen our knowledge of the pathophysiology of AD and T2DM based on preclinical studies and provide helpful hints for future research, such as whether GALR2 agonists might be determined as a potential therapeutic approach to treat both conditions.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"116 ","pages":"Article 102586"},"PeriodicalIF":2.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of vasoactive intestinal peptide on neuroexcitability of female-specific subpopulation of myelinated Ah-type neurons isolated from trigeminal ganglia of adult female rats","authors":"Feng Yan ,&nbsp;Pan Zhong-xuan ,&nbsp;Tan Li-li ,&nbsp;Fang Luo ,&nbsp;Ding Hai-ying","doi":"10.1016/j.npep.2025.102569","DOIUrl":"10.1016/j.npep.2025.102569","url":null,"abstract":"<div><div>Migraine headache remains a health issue more commonly seen in women with a complicated pathophysiology and is under debate. Vasoactive intestinal peptide (VIP) is a potential factor associated with trigeminovascular system. Here, trigeminal ganglion (TG) neurons were isolated from adult female rats and action potentials (AP) from identified myelinated Ah-type were recorded before and after treatment with VIP with or without blockers using whole-cell patch-clamp technique. The results showed that VIP 100 nM induced a significant increase in the firing frequency of repetitive discharge in these Ah-type TG neurons with dramatic narrowed AP, increased rate of derivative of down-stroke velocity, and deeper after-hyperpolarization (AHP), and these alternations could be reversed by Iberiotoxin except for AHP that was abolished by Apamin. Strikingly, VIP-mediated increase in firing frequency of AP and waveform characters of repolarization were completely blocked by PG97–269, rather that PG-99-465. Interestingly, PG97–269 alone could also slightly but markedly reduced repetitive firing of Ah-type TG neurons under control condition. Taken all these data together, we conclude that VIP upregulates the neuroexcitability of female-specific Ah-type neurons via presumable VPAC1 activation that plays a minor role in the development of basal neuroexcitation and the dataset adds valuable insights into the etiology of migraine headache.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"115 ","pages":"Article 102569"},"PeriodicalIF":2.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145555264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual role of Kisspeptin-10 in modulating neuroinflammation: Downregulation of NLRP3 inflammasome activation and Caspase-1-mediated pyroptosis, and activation of BAG3-dependent aggrephagy in microglial cells","authors":"Ömer Faruk Kalkan ,&nbsp;Şeniz Erdem ,&nbsp;Mehmet Erdem ,&nbsp;Satinur Ateşer Kalkan ,&nbsp;Zafer Şahin ,&nbsp;Ali Yavuz Uzun ,&nbsp;Abdullah Kaan Kurt ,&nbsp;Süleyman Caner Karahan","doi":"10.1016/j.npep.2025.102580","DOIUrl":"10.1016/j.npep.2025.102580","url":null,"abstract":"<div><h3>Background</h3><div>Microglial NLRP3 inflammasome activation plays a central role in the neuroinflammatory cascade that contributes to the pathogenesis of various neurodegenerative diseases. Activation of the canonical inflammasome pathway leads to caspase-1 activation, gasdermin D (GSDMD) cleavage, and pyroptotic cell death, along with the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18). Kisspeptin-10 (KP-10), a bioactive neuropeptide of the kisspeptin family, has been shown to exert regulatory effects on immune function; however, its role in neuroinflammation process remains unclear. In this study, we investigated the effects of KP-10 on LPS + ATP-induced NLRP3 inflammasome activation and pyroptotic signaling in murine microglial cells.</div></div><div><h3>Results</h3><div>KP-10 treatment significantly reduced NLRP3 expression, inhibited cleavage of caspase-1 into its active p20 subunit, and decreased GSDMD cleavage into its pore-forming N-terminal fragment (GSDMD-N), indicating suppression of inflammasome-dependent pyroptosis. KP-10 also attenuated the secretion of IL-1β and IL-18, confirming functional inhibition of the inflammasome pathway. Mechanistically, KP-10 markedly upregulated Bcl-2-associated athanogene 3 (BAG3), a key co-chaperone involved in selective autophagy.</div></div><div><h3>Conclusion</h3><div>These findings demonstrate that KP-10 suppresses microglial pyroptosis and neuroinflammatory signaling through dual mechanisms: inhibition of the NLRP3–caspase-1–GSDMD axis and activation of BAG3-dependent selective autophagy. This study identifies KP-10 as a novel modulator of microglial inflammasome activity and highlights its therapeutic potential for treating neuroinflammatory and neurodegenerative disorders.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"115 ","pages":"Article 102580"},"PeriodicalIF":2.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145733308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the efficacy of neurotensin receptor-1 antagonist SR48692 in high-fat diet-induced neurotoxicity in mice: An in vivo study","authors":"Pradeep Verma,&nbsp;Himanshu Pal,&nbsp;Banalata Mohanty","doi":"10.1016/j.npep.2025.102581","DOIUrl":"10.1016/j.npep.2025.102581","url":null,"abstract":"<div><div>Overconsumption of high-calorie foods has been linked with enhanced peripheral Neurotensin (NT) secretion. The elevated endogenous NT participates in lipid absorption in the gastrointestinal tract. An impaired neurotensinergic system leads to metabolic dysregulation, which creates systemic inflammation and oxidative stress, considered risk factors for neurodegeneration. NT receptor-1 (NTR1) antagonist, SR48692, might restrict fat absorption via inhibiting the NT signalling and, thereby, mitigating the neurotoxic effects of high-fat diet (HFD)-induced lipid dysregulation. The present study investigated the neuroprotective effect of SR48692 against HFD-induced alterations in lipid profile and imbalanced redox status. In this study, 36 male Swiss mice were randomly assigned to six groups and were injected intraperitoneally with saline or SR48692 for 4 weeks: group I/regular chow diet (CD); group II/CD + SR48692 100 μg/kg b.w. (SR_L); group III/CD + SR48692 400 μg/kg b.w. (SR_H); group IV/HFD; group V/HFD + SR_L; and group VI/HFD + SR_H. Co-treatment with SR_L showed improvements concerning lipid metabolic dysregulation and redox balance, as evidenced by decreased triglycerides, total cholesterol, low-density lipoprotein cholesterol, and leptin, and increased high-density lipoprotein cholesterol and antioxidants, observed in hippocampal histomorphometry as modulation in hippocampal cell layer thickness and density. Co-treatment with SR_H showed more detrimental effects than HFD in all studied parameters. Similarly, the CD groups treated with both doses of SR48692 showed exacerbated detrimental effects compared to the CD. Collectively, these findings suggested that only SR_L showed an ameliorating effect on HFD-induced neurodegeneration. The differential effectiveness of both doses of SR48692 co-treatment in mitigating neurodegeneration via improvement in lipid dysregulation might be due to NTR2 and/or NTR3-mediated lipid absorption.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"115 ","pages":"Article 102581"},"PeriodicalIF":2.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulating neuropeptide Y pathways to combat nicotine addiction through emerging evidence and future directions","authors":"Sameer Khidkikar ,&nbsp;Divya Malode ,&nbsp;Brijesh Taksande ,&nbsp;Mayur Kale ,&nbsp;Jayshree Taksande ,&nbsp;Mohammad Qutub ,&nbsp;Amol Tatode ,&nbsp;Milind Umekar","doi":"10.1016/j.npep.2025.102584","DOIUrl":"10.1016/j.npep.2025.102584","url":null,"abstract":"<div><div>Nicotine addiction constitutes a significant global health burden, primarily driven by the substance's capacity to dysregulate the brain's reward and stress systems. This chronic relapsing disorder is characterized by robust dependence and high rates of relapse, underscoring the limitations of current therapeutic strategies. Neuropeptide Y (NPY), a 36-amino acid neuromodulator abundantly expressed in the central nervous system, has emerged as a critical regulator of emotional behavior, stress responses, and reward pathways. Its role in the pathophysiology of nicotine addiction is of increasing interest. NPY exerts its pleiotropic effects via G-protein-coupled receptors (Y1, Y2, and Y5), which are strategically positioned to modulate stress-related circuits and attenuate the hyper-dopaminergic state induced by nicotine in the mesolimbic system. Chronic nicotine exposure disrupts endogenous NPYergic signaling in key neuroanatomical loci such as the amygdala and prefrontal cortex, a neuroadaptation that heightens stress sensitivity and addiction vulnerability. The consequent reduction in NPY tone during withdrawal exacerbates the negative affective states of anxiety and stress, precipitating relapse. Preclinical evidence indicates that therapeutic strategies targeting NPY pathways including receptor-specific agonists, gene therapy for region-specific overexpression, and advanced peptide delivery systems show considerable promise for mitigating withdrawal symptomatology and reducing nicotine-seeking behavior. This review synthesizes the compelling preclinical and emerging human evidence supporting the NPY system as a therapeutic target, highlighting the critical need to develop novel, brain-penetrant NPY receptor agonists and biomarkers to bridge the translational gap and improve clinical outcomes for nicotine dependence.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"115 ","pages":"Article 102584"},"PeriodicalIF":2.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}