biostudies-literatureHahn NGerman Science Foundation (DFG)e70207https://www.ebi.ac.uk/biostudies/studies/S-EPMC12409108biostudies-literatureUnknown169(9)Erythropoietin (Epo) and its non-erythropoietic splice variant EV-3 have demonstrated potent neuroprotective effects across species, although the respective mechanisms are variable and incompletely understood. Unlike vertebrates, insects lack both Epo and the classical Epo receptor but express Cytokine Receptor-Like Factor 3 (CRLF3), a conserved type I receptor that serves as a neuroprotective receptor for Epo and EV-3 in insects and human iPSC-derived neuron-like 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 Locusta migratoria demonstrated that human Epo and EV-3 prevented hypoxia-induced apoptosis via actJournal of neurochemistryMultiple Mammalian Cytokines and Erythropoietin-Mimetic Peptides Protect Insect Neurons via Phylogenetically Conserved Cytokine Receptor-Like Factor 3 (CRLF3).PMC12409108HE 3301/5-1HE 3301/6-1Pauls SJahn OKnorr DYWerven LVTrebilcock ASchwedhelm-Domeyer NHahn NHuang REhrenreich HTwellsieck BHeinrich RfalseMultiple Mammalian Cytokines and Erythropoietin-Mimetic Peptides Protect Insect Neurons via Phylogenetically Conserved Cytokine Receptor-Like Factor 3 (CRLF3).Erythropoietin (Epo) and its non-erythropoietic splice variant EV-3 have demonstrated potent neuroprotective effects across species, although the respective mechanisms are variable and incompletely understood. Unlike vertebrates, insects lack both Epo and the classical Epo receptor but express Cytokine Receptor-Like Factor 3 (CRLF3), a conserved type I receptor that serves as a neuroprotective receptor for Epo and EV-3 in insects and human iPSC-derived neuron-like 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 Locusta migratoria demonstrated that human Epo and EV-3 prevented hypoxia-induced apoptosis via act2025-01-01T00:00:00Z2025 Sep2026-05-29T21:50:51.473Z2026-04-08T06:08:44.844ZS-EPMC124091084090388110.1111/jnc.70207