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Unlike vertebrates, insects lack both Epo and the classical Epo receptor but express Cytokine Receptor\u2010Like Factor 3 (CRLF3), a conserved type I receptor that serves as a neuroprotective receptor for Epo and EV\u20103 in insects and human iPSC\u2010derived neuron\u2010like cells. Insects, which express CRLF3 but lack all other group 1 type I cytokine receptors, represent a suitable model to study the function of CRLF3 in neuroprotection. Previous experiments with primary brain neurons from the locust\n                    <jats:italic>Locusta migratoria<\/jats:italic>\n                    demonstrated that human Epo and EV\u20103 prevented hypoxia\u2010induced apoptosis via activation of CRLF3 and downstream signaling mediated by JAK\/STAT activity. Here we demonstrate that locust neurons are also protected by three small peptides (\u2264\u200920 amino acids) with previously established erythropoietic and\/or neuroprotective capacities in mammals. These peptides included non\u2010erythropoietic HBSP and P16, as well as erythropoietic EMP1. To further characterize the ligand spectrum of locust CRLF3, we tested specific ligands of vertebrate group 1 type I cytokine receptors for their neuroprotective potential. While human thrombopoietin protected locust neurons via activation of CRLF3, human prolactin and growth hormone showed no anti\u2010apoptotic effects. Our findings highlight CRLF3 as a versatile neuroprotective receptor that can be activated by the three natural human cytokines Epo, EV\u20103, and thrombopoietin, and three artificial short peptides with and without erythropoietic activity. In contrast to vertebrate classical Epo receptor, which is only activated by Epo and EMP1, CRLF3 has an extended and more generalist ligand spectrum to mediate neuroprotection. This wide ligand spectrum may support the hypothesis of CRLF3 being the evolutionary precursor of various vertebrate\u2010specific cytokine receptors and may qualify this more general cell protective receptor as a target for pharmacological intervention in neurodegenerative processes.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70207-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70207","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T05:20:56Z","timestamp":1756963256000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multiple Mammalian Cytokines and Erythropoietin\u2010Mimetic Peptides Protect Insect Neurons via Phylogenetically Conserved Cytokine Receptor\u2010Like Factor 3 (\n                    <scp>CRLF3<\/scp>\n                    )"],"prefix":"10.1111","volume":"169","author":[{"given":"Nina","family":"Hahn","sequence":"first","affiliation":[{"name":"Section of Translational Neuroimmunology, Department of Neurology and Center for Sepsis Control and Care Jena University Hospital  Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debbra Y.","family":"Knorr","sequence":"additional","affiliation":[{"name":"Basic &amp; Clinical Neuroscience Department King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Twellsieck","sequence":"additional","affiliation":[{"name":"Cellular Neurobiology, Institute for Zoology and Anthropology Georg\u2010August\u2010University G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9496-688X","authenticated-orcid":false,"given":"Ruoyu","family":"Huang","sequence":"additional","affiliation":[{"name":"Werner Reichardt Centre for Integrative Neuroscience, Institute of Neurobiology University of T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Trebilcock","sequence":"additional","affiliation":[{"name":"Cellular Neurobiology, Institute for Zoology and Anthropology Georg\u2010August\u2010University G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Schwedhelm\u2010Domeyer","sequence":"additional","affiliation":[{"name":"Cellular Neurobiology, Institute for Zoology and Anthropology Georg\u2010August\u2010University G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Pauls","sequence":"additional","affiliation":[{"name":"Cellular Neurobiology, Institute for Zoology and Anthropology Georg\u2010August\u2010University G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars v.","family":"Werven","sequence":"additional","affiliation":[{"name":"Neuroproteomics Group, Department of Molecular Neurobiology Max\u2010Planck\u2010Institute for Multidisciplinary Sciences  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Jahn","sequence":"additional","affiliation":[{"name":"Neuroproteomics Group, Department of Molecular Neurobiology Max\u2010Planck\u2010Institute for Multidisciplinary Sciences  G\u00f6ttingen Germany"},{"name":"Translational Neuroproteomics Group, Department of Psychiatry and Psychotherapy University Medical Center G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannelore","family":"Ehrenreich","sequence":"additional","affiliation":[{"name":"Experimental Medicine, Central Institute of Mental Health, Medical Faculty Mannheim Heidelberg University  Heidelberg Germany"},{"name":"Clinical Neuroscience Max\u2010Planck\u2010Institute for Experimental Medicine  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8369-0507","authenticated-orcid":false,"given":"Ralf","family":"Heinrich","sequence":"additional","affiliation":[{"name":"Cellular Neurobiology, Institute for Zoology and Anthropology Georg\u2010August\u2010University G\u00f6ttingen  G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1210\/edrv\u201012\u20104\u2010424"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021013113"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574\u2010019\u20100194\u20106"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/PL00000901"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201003167\u20100"},{"key":"e_1_2_12_8_1","unstructured":"Bonnas C. 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