Peptides最新文献

{"title":"Erythropoietin-derived peptide (HBSP) inhibits caspase-3/GSDME through HMGB1 to regulate pyroptosis and reduce diabetic retinopathy","authors":"Zhiyong Zheng,&nbsp;Qing Liu,&nbsp;Xu Chen,&nbsp;Muzhen Huang,&nbsp;Qing Ye,&nbsp;Min Chen","doi":"10.1016/j.peptides.2026.171520","DOIUrl":"10.1016/j.peptides.2026.171520","url":null,"abstract":"<div><h3>Background</h3><div>Pyroptosis exerts an important effect on the development of diabetic retinopathy (DR). Helix B surface peptide (HBSP) is derived from erythropoietin (EPO) and has a special role in diabetes. This study explored effect of HBSP on retinal pigment epithelium (RPE) cell pyroptosis in DR and its mechanism.</div></div><div><h3>Methods</h3><div>ARPE-19 cells were treated with high-glucose (HG) and HBSP. Mice were injected with streptozotocin (STZ) and treated with HBSP. HE staining analyzed pathological changes. EB staining tested integrity of blood-retinal barrier (BRB). RT-qPCR determined HMGB1 mRNA. Western blot detected HMGB1 and pyroptosis-related proteins (NLRP3, caspase-1, GSDMD, caspase-3, GSDME). CCK-8 determined viability of ARPE-19 cells. Changes of cell pyroptosis were observed by transmission electron microscopy.</div></div><div><h3>Results</h3><div>In STZ-induced diabetic mice, retinal tissue exhibited typical DR lesion, BRB breakdown and increased pyroptosis-related proteins. HG reproduced these events in ARPE-19 cells: viability loss, ultrastructural pyroptotic morphology and activation of both canonical (caspase-1/GSDMD) and non-canonical (caspase-3/GSDME) pyroptotic pathways, with the latter being most pronounced. HBSP dose-dependently rescued retinal architecture, restored BRB integrity <em>in vivo</em>, and normalized HG-lowered cell viability <em>in vitro</em>. HBSP ameliorated HG-triggered pyroptosis, primarily by suppressing caspase-3/GSDME signaling pathway. HBSP alleviated HG-stimulated pyroptosis via downregulating HMGB1. HMGB1 knockdown alleviated HG-triggered pyroptosis, primarily by inhibiting caspase-3/GSDME signaling pathway. <em>In vivo</em>, overexpression of HMGB1 could reverse the therapeutic effect of HBSP and increase pyroptosis.</div></div><div><h3>Conclusion</h3><div>HBSP suppresses RPE cell pyroptosis by disrupting the HMGB1-caspase-3/GSDME axis, thereby mitigating DR. These findings could illuminate a promising therapeutic avenue for DR.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"201 ","pages":"Article 171520"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149031192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthetic host defence peptides modulate phagocytic activity and release of inflammatory mediators by BV-2 microglial cells","authors":"Ishvin Riar,&nbsp;Tyler J. Wenzel,&nbsp;Robert E.W. Hancock,&nbsp;Andis Klegeris","doi":"10.1016/j.peptides.2026.171525","DOIUrl":"10.1016/j.peptides.2026.171525","url":null,"abstract":"<div><div>Microglia are the predominant resident innate immune cells of the brain that maintain homeostasis and mitigate damage caused by injury and pathogens. Synthetic variants of host defence peptides, also termed antimicrobial peptides, are designed based on their endogenous counterparts and have been demonstrated to exhibit enhanced immunomodulatory activities, including an ability to selectively modulate the release of cytokines by monocytic cells. These peptides exert therapeutic benefits in a murine brain injury model, but it is unknown whether they can modulate microglial immune responses. We tested the effects of three host defence peptides, namely innate defence regulators (IDR)-1002, IDR-1018 and D-3006, on selected functions of BV-2 murine microglial cells, as well as differentiated HL-60 monocytic cells, which were used as a human model of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) production. It was demonstrated here that IDR-1002, IDR-1018 and D-3006 reduced the production of nitric oxide, tumor necrosis factor-α (TNF), ROS, and cytotoxic factors, depending on whether the cells were stimulated with lipopolysaccharide (LPS), interferon (IFN)-γ, or their combination. All three IDRs also reduced LPS-induced phagocytic activity of BV-2 microglia, while IDR-1018 and D-3006 increased this function in unstimulated cells, though our findings are limited to cell lines and require validation in primary or human microglia. By altering selected inflammatory, cytotoxic, and phagocytic readouts of microglial cells in a context-dependent manner, synthetic host defence peptides such as IDRs warrant further investigation as candidate modulators of neuroinflammation, including in animal models of relevant neurological disorders.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"201 ","pages":"Article 171525"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bidirectional pharmacology of GIP receptor targeting in obesity: Historical foundations, mechanistic divergence, and translational boundaries","authors":"Chenming Liu,&nbsp;Yanghai Wang,&nbsp;Jingli Liu,&nbsp;Peirong Tian,&nbsp;Jia Liu,&nbsp;Mengyi Li,&nbsp;Zhongtao Zhang,&nbsp;Peng Zhang","doi":"10.1016/j.peptides.2026.171524","DOIUrl":"10.1016/j.peptides.2026.171524","url":null,"abstract":"<div><div>The glucose-dependent insulinotropic polypeptide receptor (GIPR) has emerged as a central target in next-generation anti-obesity drug development. Its pharmacology, however, presents an apparent paradox: sustained GIPR agonism and GIPR antagonism can both lower body weight, and both can augment weight loss produced by glucagon-like peptide-1 receptor (GLP-1R) agonism. For this structured narrative review, PubMed/MEDLINE and ClinicalTrials.gov were searched from database inception through 1 August 2026 using prespecified terms for receptors, interventions, obesity, and bariatric surgery to identify basic, translational, and clinical studies available. Retrieved records underwent staged title/abstract screening and full-text eligibility assessment. The evidence was integrated across three levels: selective GIPR modulation, combined GIPR and GLP-1R modulation, and applications after metabolic and bariatric surgery. Recent rodent studies support a working model in which long-acting GIPR agonism engages GABAergic and area-postrema-related circuits, whereas the added weight-lowering effect of GIPR antagonism in several GLP-1R-containing combination models depends on intact GLP-1R signaling and hypothalamic GIPR networks. These mechanisms remain incompletely validated in humans. Clinically, tirzepatide has demonstrated the efficacy of GIPR/GLP-1R co-agonism, whereas maridebart cafraglutide provides phase 2 evidence for GIPR antagonism combined with GLP-1R agonism; nevertheless, the efficacy of these multi-receptor agents cannot be attributed simply to a single GIPR component. Metabolic and bariatric surgery is discussed as a translational context in which altered incretin physiology limits direct extrapolation from nonsurgical obesity trials. Future studies should use stratified designs grounded in receptor pharmacology, brain-region specificity, type of bariatric procedure, and postoperative metabolic phenotype, while assessing fat mass, lean mass, hepatic fat, bone metabolism, gastrointestinal tolerability, hypoglycemia, and weight regain after treatment withdrawal.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"201 ","pages":"Article 171524"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149113170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IGF2BP3 drives macrophage M1 polarization to promote intracranial aneurysm rupture through m6A-mediated NPY1R stabilization","authors":"Jian He,&nbsp;Ting Tang,&nbsp;Yonghong Duan,&nbsp;Richu Liang,&nbsp;Min Zhou,&nbsp;Bing Wang,&nbsp;Yuanding Jiang","doi":"10.1016/j.peptides.2026.171522","DOIUrl":"10.1016/j.peptides.2026.171522","url":null,"abstract":"<div><h3>Background</h3><div>The progression of intracranial aneurysm (IA) was closely associated with an imbalance in M1/M2 macrophage polarization. Neuropeptide Y receptor 1 (NPY1R) was involved in regulating IA development. However, NPY1R in IA-associated macrophages and its impact on macrophage polarization remain to be elucidated.</div></div><div><h3>Methods</h3><div>Macrophage polarization levels were analyzed by flow cytometry. Molecular expression was detected using RT-qPCR, western blot, and IF assay. Global m⁶A modification levels were measured by colorimetric assay. Cytokine secretion was measured by ELISA. The interaction between Igf2bp3 and <em>Npy1r</em> mRNA was confirmed by RNA pull-down and RIP assays. Pathological changes in cerebral arteries were examined using HE staining.</div></div><div><h3>Results</h3><div>In IA progression, macrophages exhibited increased M1 polarization, accompanied by elevated NPY1R expression and m⁶A modification levels. NPY1R then activated the PI3K/STAT3 pathway to promote macrophage M1 polarization and pro-inflammatory cytokine secretion. Macrophage-specific NPY1R knockout alleviated IA formation and reduced rupture risk by inhibiting M1 polarization. Mechanistically, Igf2bp3 bound to <em>Npy1r</em> mRNA to enhance its stability through m⁶A modification, thereby upregulating <em>Npy1r</em> expression. Igf2bp3 knockdown most effectively decreased <em>Npy1r</em> expression, suppressed M1 polarization, and inactivated the PI3K/STAT3 pathway, whereas NPY1R overexpression reversed these effects.</div></div><div><h3>Conclusion</h3><div>IGF2BP3 promoted macrophage M1 polarization and aggravated IA formation by enhancing <em>Npy1r</em> mRNA stability via m⁶A modification to activate the PI3K/STAT3 pathway.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"201 ","pages":"Article 171522"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antimicrobial peptide databases: A detailed comparison and complementary features","authors":"Erfan Zamani,&nbsp;Mohammadhossein Ghazizadeh-Ahsaei,&nbsp;Yasaman Mahmoodi,&nbsp;Faramarz Mehrnejad","doi":"10.1016/j.peptides.2026.171523","DOIUrl":"10.1016/j.peptides.2026.171523","url":null,"abstract":"<div><div>Antimicrobial peptides (AMPs) have garnered considerable attention as promising alternatives to conventional antibiotics, resulting in extensive experimental and computational studies that have generated large volumes of data on peptide sequences, biological activities, structural features, and experimental conditions. To organize and facilitate the use of these data, several AMP databases have been developed; however, they differ markedly in scope, data organization, annotation depth, searchability, data accessibility, usability, and support for computational analysis. In this review, we critically compare five widely used general AMP databases—APD, CAMP, DBAASP, dbAMP, and DRAMP—by analyzing database publications and directly evaluating their current data content, web interfaces, search systems, analytical tools, and suitability for different research workflows. The comparison shows that no single database fully addresses all research needs, as the resources offer complementary strengths in biological annotation, sequence and family analysis, experimental activity data, computational discovery, and therapeutic-development information. These findings highlight the need for more standardized and interoperable database strategies that improve data consistency, annotation quality, searchability, tool reliability, and the comparison, integration, and reuse of AMP data in experimental and computational research.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"201 ","pages":"Article 171523"},"PeriodicalIF":3.5,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelin-1 modulates hippocampal and hypothalamic neuronal network activity in mouse primary dissociated cultures and brain slices","authors":"Lea Wegmann ,&nbsp;Morris Haid ,&nbsp;Dennis Thomassen ,&nbsp;Olga A. Sergeeva","doi":"10.1016/j.peptides.2026.171495","DOIUrl":"10.1016/j.peptides.2026.171495","url":null,"abstract":"<div><div>Endothelin-1 (ET-1) is known not only as a vasoconstrictor, but also as a neuromodulator. It can reset the circadian clock and we hypothesized that it modulates neuronal excitability and network activity in histaminergic neurons (HN). HN, located in the tuberomammillary nucleus (TMN) of the caudal hypothalamus (cHPT), fire spontaneously during waking and promote arousal. Previous studies have shown that ET-1 reduces firing frequency of hippocampal pyramidal neurons, whereas its effects on electrophysiological properties of HN remain unknown. We now studied the expression of ET-receptors (ET_A and ET_B) in the hippocampus (HPC) and caudal hypothalamus by single-cell RT-PCR and qPCR. The responses to ET-1 were studied in HN and dentate gyrus granule cells (DGgc) of brain slices using patch-clamp recordings and primary cultures of cHPT and HPC using Microelectrode Arrays (MEAs).</div><div>ET-1 significantly decreased firing frequency in HPC and increased it in cHPT cultures with prevailing inhibition of individual MEA channels in HPC and excitation in cHPT. Neuronal synchrony and bursting were significantly increased in cHPT. Relative to HPC, cHPT displayed higher expression of ET_B. In brain slices, ET-1 induced a delayed bosentan-sensitive increase in HN and decrease in DGgc firing frequency. HN expressed ET_B (15 of 22 HN) and ET_A (4 of 15 ET_B positive HN), whereas only ET_B was expressed in 50% of DGgc.</div><div>We conclude that ET-1 differentially modulates cHPT and HPC. By exciting HN and synchronizing neuronal network activity in cHPT, ET-1 may contribute to cellular and circuit-level mechanisms in the regulation of arousal and wakefulness.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"198 ","pages":"Article 171495"},"PeriodicalIF":2.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148055114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 Kiss1 neurons in regulating metabolism and energy balance","authors":"Lingyu Sun ,&nbsp;Ruidong Gao ,&nbsp;Jing Chen","doi":"10.1016/j.peptides.2026.171497","DOIUrl":"10.1016/j.peptides.2026.171497","url":null,"abstract":"<div><div>Hypothalamic kisspeptin, encoded by the <em>Kiss1</em> gene, serves as an important regulator of the reproductive axis and sexual maturation. Since reproductive physiology is tightly coupled to metabolic cues, metabolic status exerts significant influence on puberty and fertility. Emerging evidence identifies kisspeptin signaling as a key determinant of central energy homeostasis. This review focuses on distinct Kiss1 neuronal populations in the arcuate nucleus of hypothalamus (Arc) and anteroventral periventricular/periventricular nucleus (AVPV/PeN) in regulating energy balance. Arc Kiss1 neurons suppress appetite via activation of POMC neurons and inhibition of AgRP/NPY neurons, while enhance energy expenditure through excitatory projections to the PVN and DMH. In contrast, AVPV/PeN Kiss1 neurons primarily exert inhibitory GABAergic regulation on PVN and DMH neurons. This indicates their suppressive modulatory function, which generally opposes the excitatory metabolic effects mediated by Arc Kiss1 neurons. Peripheral metabolic hormones, including leptin, adiponectin, insulin, and ghrelin, dynamically modulate Kiss1 neuronal activity through direct receptor or indirect POMC/AgRP pathways. By integrating these peripheral signals, Kiss1 neurons act as important modulators of metabolic homeostasis. Taken together, these findings indicate that Kiss1 neuronal pathway may be worth additional investigation in the field of metabolic disorders.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"198 ","pages":"Article 171497"},"PeriodicalIF":2.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148219339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scorpion venom peptide Hp1412 restricts enveloped virus replication by dampening virion infectivity","authors":"Gang Xu ,&nbsp;Na Yang ,&nbsp;Jing Yang,&nbsp;Yiqi Li,&nbsp;Zhijian Cao","doi":"10.1016/j.peptides.2026.171498","DOIUrl":"10.1016/j.peptides.2026.171498","url":null,"abstract":"<div><div>The majority of viruses considered as pandemic threats are enveloped viruses, structurally defined by lipids and integral viral envelope proteins. Scorpion venom contains an extremely diverse set of bioactive peptides, especially rich in antimicrobial agents. Here, we identified a 68-amino acid antimicrobial precursor protein Hp1412 from the venom gland of the scorpion <em>Heterometrus petersii</em>. Its 13-residue mature peptide was chemically synthesized and biochemically characterized. <em>In vitro</em> experiments demonstrated that Hp1412 exerted concentration-dependent inhibition on HCV RNA expression and exhibited low cell cytotoxicity. This peptide acted exclusively at the free virion stage of the HCV infection cycle, with optimal antiviral activity observed at 37°C. Further investigations revealed that Hp1412 possessed broad-spectrum antiviral activity against the tested enveloped viruses including IAV, HSV-1, VSV and SeV, whereas no significant inhibitory effect was observed against the non-enveloped virus EV71. These results suggested that the antiviral activity of Hp1412 was enveloped virus specific, and its underlying mechanism might involve direct interaction with free enveloped viral particles to disrupt their envelope structure. Further transmission electron microscopy analysis showed that Hp1412 inactivates IAV by directly disrupting the virion envelope. <em>In vivo</em> experiments showed that Hp1412 could prophylactically inhibit IAV replication in the lung tissues of mice, and significantly alleviate the excessive activation of innate immune responses and inflammatory reactions induced by IAV infection in lung tissues. Our study offers an initial clue that may inform the future development of broad-spectrum drugs for the prevention of enveloped virus infections.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"198 ","pages":"Article 171498"},"PeriodicalIF":2.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148219265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuregulin 4 improves white adipose tissue inflammation in mice with polycystic ovary syndrome","authors":"Xi Wang ,&nbsp;Meiqi Feng ,&nbsp;Lingshan Hu,&nbsp;Xiaohan Li,&nbsp;Sili Guo,&nbsp;Haibo Xue,&nbsp;Lei Zhang","doi":"10.1016/j.peptides.2026.171496","DOIUrl":"10.1016/j.peptides.2026.171496","url":null,"abstract":"<div><h3>Background</h3><div>Neuregulin 4 (Nrg4), a secretory peptide predominantly derived from brown adipose tissue (BAT), has been verified to play roles in multiple metabolic disorders. Nevertheless, the role of Nrg4 in the pathogenesis of PCOS remains largely unelucidated.</div></div><div><h3>Methods</h3><div>Female C57BL/6 J mice were randomly divided into NC, PCOS, AAV-Luc, and AAV-Nrg4 group. Mice in the AAV-Luc group received AAV-Luc injection, while those in the AAV-Nrg4 group received AAV-Nrg4 injection into the BAT in the scapular region. One week after virus injection, the PCOS model was established. The weight, intraperitoneal glucose tolerance test and serum sex hormone were detected at the eighth week after virus injection. Then, the mice were sacrificed. The expression of Nrg4 in BAT was detected. The histological morphology of the ovaries and and WAT were observed. The expression of steroid synthasesin the ovaries, inflammatory factors and adiponectin in WAT were detected. Further, the expression of macrophage polarization markers in WAT were measured. Finally, the ErbB4/PI3K/AKT signaling pathway related proteins were detected.</div></div><div><h3>Results</h3><div>In PCOS mice, overexpression of Nrg4 in BAT led to reduction of body weight, improvement of glucose tolerance, restoration of the estrous cycle, and decrease in serum testosterone estrogen and luteinizing hormone levels. This treatment also reduced the levels of pro-inflammatory factors. Additionally, Nrg4 overexpression suppressed the expression of CYP17A1 and StAR in ovarian tissue and enhanced the expression of CYP19A1. Finally, the ErbB4/PI3K/AKT signaling pathway was intensely activated in WAT.</div></div><div><h3>Conclusion</h3><div>Nrg4 can improve WAT inflammation and ovarian steroidogenesis and follicular development in PCOS mice.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"198 ","pages":"Article 171496"},"PeriodicalIF":2.9,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148219145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-based rational design of high-affinity JAZF1 variants peptides to target the testicular orphan nuclear receptor 4 and pro-opiomelanocortin axis in Cushing’s disease","authors":"Wang Guoguo,&nbsp;Su Meng","doi":"10.1016/j.peptides.2026.171500","DOIUrl":"10.1016/j.peptides.2026.171500","url":null,"abstract":"<div><div>The regulation of <em>pro-opiomelanocortin (Pomc)</em> expression by the testicular orphan receptor 4 (TR4) constitutes a critical mechanism underlying the pathogenesis of Cushing’s disease (CD). Although the endogenous repressor <em>juxtaposed with another zinc finger gene 1 (JAZF1)</em> inhibits TR4 activity, its relatively low binding affinity (<em>K</em>_D = 2246 nM) limits its therapeutic potential. In this study, we employed an iterative structure-based lead optimization strategy to enhance the JAZF1 scaffold. Utilizing Discovery Studio for virtual screening, we conducted successive rounds of in silico saturation mutagenesis, ranging from single point to multi-site combinatorial substitutions, which were subsequently validated through incremental experimental binding assays. This recursive optimization process led to the identification of two triple-mutant JAZF1 peptides (V56L/A68Y/A69R and D67L/A68Y/A69R) exhibiting more than a 2,200-fold enhancement in TR4 binding affinity. These engineered peptides, along with high-affinity small molecules such as nilotinib (<em>K</em>_D = 4.83 nM), effectively downregulated <em>Pomc</em> expression and inhibited proliferation of AtT-20 tumor cells. Taken together, these findings suggest that the JAZF1-TR4-Pomc axis may serve as a potential therapeutic target for modulating adrenocorticotropic hormone (ACTH) hypersecretion in CD.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"198 ","pages":"Article 171500"},"PeriodicalIF":3.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148259167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}