{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T05:21:09Z","timestamp":1763529669045,"version":"3.45.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Atopic dermatitis (AD) is a long-standing inflammatory dermatosis marked by intense itching and immune imbalance. Despite recent advances in targeted biologic therapies, limitations in efficacy and cost highlight the urgent need for novel therapeutic targets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed Mendelian randomization (MR) by combining genome-wide association studies (GWAS), expression quantitative trait loci (eQTL), and protein QTL (pQTL) datasets to identify causal druggable genes associated with AD. To enhance the validity of causal inference, we further utilized colocalization and summary-data-based MR (SMR) techniques. We validated the expression of five prioritized genes using reverse transcription quantitative PCR (RT-qPCR), performed on RNA extracted from the peripheral blood of AD patients and healthy controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The MR approach revealed 32 candidate genes with potential druggable properties linked to AD, with 12 showing strong colocalization signals (posterior probability of hypothesis 4 (PP.H4)\u202f&amp;gt;\u202f0.8). The pQTL analysis indicated that increased plasma NMB levels were associated with a heightened risk of AD (OR\u202f=\u202f1.18,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f3.29\u202f\u00d7\u202f10^-8), a conclusion further corroborated by SMR analysis. RT-qPCR confirmed significantly elevated expression of\n                      <jats:italic>NMB, IL2RA, IL1RL1, and PRKCQ<\/jats:italic>\n                      in the peripheral blood samples of AD patients. Additionally, MR studies demonstrated that NMB was associated with bullous pemphigoid and urticaria.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Integrative MR and PCR validation across Icelandic, Finnish and Chinese samples nominates NMB as a candidate AD target. These preliminary, multi-ancestry signals now require replication in large, population-matched cohorts before any therapeutic translation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2025.1660249","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T05:18:05Z","timestamp":1763529485000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Neuromedin B identified as a therapeutic target for atopic dermatitis: evidence from Mendelian randomization and PCR validation"],"prefix":"10.3389","volume":"12","author":[{"given":"Lingling","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxu","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunxi","family":"Ke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaolin","family":"Bu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingqing","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiang","family":"Ji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1186\/s13098-021-00749-x","article-title":"Adiponectin gene polymorphisms and risk of type 2 diabetes: an updated evidence for meta-analysis","volume":"13","author":"Alimi","year":"2021","journal-title":"Diabetol Metab Syndr"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1080\/1744666x.2021.1940962","article-title":"The IL-4, IL-13 and IL-31 pathways in atopic dermatitis","volume":"17","author":"Dubin","year":"2021","journal-title":"Expert Rev Clin Immunol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"12","DOI":"10.4168\/aair.2012.4.1.12","article-title":"Epidermal barrier in atopic dermatitis","volume":"4","author":"Kim","year":"2012","journal-title":"Allergy Asthma Immunol Res"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1111\/jdv.18345","article-title":"European guideline (EuroGuiDerm) on atopic eczema: part I - systemic therapy","volume":"36","author":"Wollenberg","year":"2022","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.3390\/microorganisms8111743","article-title":"JAK-STAT inhibitors in atopic dermatitis from pathogenesis to clinical trials results","volume":"8","author":"Szalus","year":"2020","journal-title":"Microorganisms"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"828","DOI":"10.2337\/dc22-1385","article-title":"Gastrointestinal consequences of type 2 diabetes mellitus and impaired Glycemic homeostasis: a mendelian randomization study","volume":"46","author":"Chen","year":"2023","journal-title":"Diabetes Care"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"155220","DOI":"10.1016\/j.metabol.2022.155220","article-title":"Nonalcoholic fatty liver disease and cardiovascular diseases: a mendelian randomization study","volume":"133","author":"Peng","year":"2022","journal-title":"Metabolism"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"10063","DOI":"10.18632\/aging.205917","article-title":"The causal role of immune cells on lung cancer: a bi-directional mendelian randomization (MR) study","volume":"16","author":"Zhu","year":"2024","journal-title":"Aging (Albany NY)"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"n2233","DOI":"10.1136\/bmj.n2233","article-title":"Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration","volume":"375","author":"Skrivankova","year":"2021","journal-title":"BMJ"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1712","DOI":"10.1038\/s41588-021-00978-w","article-title":"Large-scale integration of the plasma proteome with genetics and disease","volume":"53","author":"Ferkingstad","year":"2021","journal-title":"Nat Genet"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1186\/s12931-024-02848-5","article-title":"Identifying potential drug targets for idiopathic pulmonary fibrosis: a mendelian randomization study based on the druggable genes","volume":"25","author":"Liu","year":"2024","journal-title":"Respir Res"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1016\/j.alit.2020.02.006","article-title":"Japanese guidelines for atopic dermatitis 2020","volume":"69","author":"Katoh","year":"2020","journal-title":"Allergol Int"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1875","DOI":"10.1016\/j.jaci.2022.03.010","article-title":"Neuroimmune communication regulating pruritus in atopic dermatitis","volume":"149","author":"Steinhoff","year":"2022","journal-title":"J Allergy Clin Immunol"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"2537","DOI":"10.1111\/jdv.19378","article-title":"Real-world effectiveness of abrocitinib treatment in patients with difficult-to-treat atopic dermatitis","volume":"37","author":"Olydam","year":"2023","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"12402","DOI":"10.1523\/jneurosci.1709-14.2014","article-title":"Cross-inhibition of NMBR and GRPR signaling maintains normal histaminergic itch transmission","volume":"34","author":"Zhao","year":"2014","journal-title":"J Neurosci"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1038\/s41583-021-00526-9","article-title":"A neuropeptide code for itch","volume":"22","author":"Chen","year":"2021","journal-title":"Nat Rev Neurosci"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"10","DOI":"10.7554\/eLife.71689","article-title":"BNP facilitates NMB-encoded histaminergic itch via NPRC-NMBR crosstalk","author":"Meng","year":"2021","journal-title":"eLife"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"175998","DOI":"10.1016\/j.ejphar.2023.175998","article-title":"Role of kainate receptors in pruriceptive processing in the mouse spinal cord","volume":"957","author":"Haruta-Tsukamoto","year":"2023","journal-title":"Eur J Pharmacol"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"2351","DOI":"10.1038\/jid.2009.98","article-title":"Canine models of atopic dermatitis: a useful tool with untapped potential","volume":"129","author":"Marsella","year":"2009","journal-title":"J Invest Dermatol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1016\/j.it.2022.09.006","article-title":"Neuro-epithelial-ILC2 crosstalk in barrier tissues","volume":"43","author":"Yin","year":"2022","journal-title":"Trends Immunol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1038\/s41590-020-0753-y","article-title":"Basophils prime group 2 innate lymphoid cells for neuropeptide-mediated inhibition","volume":"21","author":"Inclan-Rico","year":"2020","journal-title":"Nat Immunol"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1111\/exd.12685","article-title":"Modulation of HMGB1 translocation and RAGE\/NF\u03baB cascade by quercetin treatment mitigates atopic dermatitis in NC\/Nga transgenic mice","volume":"24","author":"Karuppagounder","year":"2015","journal-title":"Exp Dermatol"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1016\/j.drudis.2016.02.011","article-title":"Molecular targets of quercetin with anti-inflammatory properties in atopic dermatitis","volume":"21","author":"Karuppagounder","year":"2016","journal-title":"Drug Discov Today"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"888","DOI":"10.3892\/ijmm.2017.3296","article-title":"Anti-inflammatory effect of quercetin and galangin in LPS-stimulated RAW264.7 macrophages and DNCB-induced atopic dermatitis animal models","volume":"41","author":"Lee","year":"2018","journal-title":"Int J Mol Med"},{"key":"ref25","doi-asserted-by":"publisher","DOI":"10.15212\/bioi-2025-0073","article-title":"Mechanistic insights and therapeutic potential of quercetin in neuroprotection: a comprehensive review of pathways and clinical perspectives","author":"Grewal","year":"2025","journal-title":"BIOI"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1593264","DOI":"10.3389\/fphar.2025.1593264","article-title":"Neuroprotective potential of quercetin in Alzheimer's disease: targeting oxidative stress, mitochondrial dysfunction, and amyloid-\u03b2 aggregation","volume":"16","author":"Adnan","year":"2025","journal-title":"Front Pharmacol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1007\/s00403-002-0381-4","article-title":"Effects of metronidazole and tinidazole ointments on models for inflammatory dermatitis in mice","volume":"294","author":"Nishimuta","year":"2003","journal-title":"Arch Dermatol Res"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1016\/j.fertnstert.2015.09.001","article-title":"Sexual activity modulates shifts in TH1\/TH2 cytokine profile across the menstrual cycle: an observational study","volume":"104","author":"Lorenz","year":"2015","journal-title":"Fertil Steril"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"819","DOI":"10.4049\/jimmunol.176.2.819","article-title":"Progesterone-induced blocking factor activates STAT6 via binding to a novel IL-4 receptor","volume":"176","author":"Kozma","year":"2006","journal-title":"J Immunol"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1074\/jbc.M006059200","article-title":"Tyrosine 220 in the 5th transmembrane domain of the neuromedin B receptor is critical for the high selectivity of the peptoid antagonist PD168368","volume":"276","author":"Tokita","year":"2001","journal-title":"J Biol Chem"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"9342","DOI":"10.7150\/thno.62255","article-title":"Neuromedin B receptor stimulation of Cav3.2 T-type Ca2+ channels in primary sensory neurons mediates peripheral pain hypersensitivity","volume":"11","author":"Zhang","year":"2021","journal-title":"Theranostics"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"8686","DOI":"10.1523\/JNEUROSCI.1533-12.2012","article-title":"A nociceptive signaling role for neuromedin B","volume":"32","author":"Mishra","year":"2012","journal-title":"J Neurosci"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"172460","DOI":"10.1016\/j.ejphar.2019.172460","article-title":"Role of TRPA1 receptors in skin inflammation induced by volatile chemical irritants in mice","volume":"858","author":"Nor\u00f5es","year":"2019","journal-title":"Eur J Pharmacol"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"638325","DOI":"10.3389\/fmed.2021.638325","article-title":"Interleukin-31 as a clinical target for pruritus treatment","volume":"8","author":"Kabashima","year":"2021","journal-title":"Front Med (Lausanne)"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"10090","DOI":"10.4081\/dr.2024.10090","article-title":"Increased serum interleukin-31 levels correlate with pruritus in psoriatic patients: a cross-sectional study in Vietnam","volume":"17","author":"Nguyen","year":"2025","journal-title":"Dermatol Reports"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.3389\/fimmu.2019.01383","article-title":"Role of the pruritic cytokine IL-31 in autoimmune skin diseases","volume":"10","author":"Gibbs","year":"2019","journal-title":"Front Immunol"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1660249\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T05:18:06Z","timestamp":1763529486000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1660249\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,19]]},"references-count":36,"alternative-id":["10.3389\/fmed.2025.1660249"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2025.1660249","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,19]]},"article-number":"1660249"}}