ABSTRACTAs the α-subunit of the high-affinity receptor for the Fc portion of immunoglobulin E (FcεRIα), FcεRIα plays a central role in IgE-mediated allergic disorders and in the immunity and immunopathology of some parasitic infections. FcεRIα is specifically expressed on basophils and mast cells, but the mechanism that controls FcεRIα expression in these cells is poorly understood. In this study, we found that the natural antisense transcript (NAT) of FcεRIα (FCER1A-AS) is co-expressed with the sense transcript (FCER1A-S) in both interleukin (IL)-3-induced FcεRIα-expressing cells and in the high FcεRIα-expressing cell line MC/9. WhenFCER1A-AS is selectively knocked down by the CRISPR/RfxCas13d (CasRx) approach in MC/9 cells, the expression of bothFCER1A-S mRNA and proteins is markedly decreased. Furthermore,FCER1A-AS deficiency was also found to be associated with a lack ofFCER1A-S expressionin vivo. Correspondingly, homozygous mice deficient inFCER1A-AS demonstrated a similar phenotype toFCER1Aknockout mice inSchistosoma japonicuminfection and in IgE-FcεRIα-mediated cutaneous anaphylaxis. Thus, we uncovered a novel pathway for the control of FcεRIα expression by its co-expressed natural antisense transcript.IMPORTANCEFcεRIα is responsible for high-affinity binding with the Fc portion of IgE, which is critical for IgE-dependent disease responses such as allergy responses and anti-parasite immunity. FcεRIα is expressed on a few cell types, including mast cells and basophils. Although the expression of FcεRIα is known to be promoted by the IL-3-GATA-2 pathway during its differentiation, the mechanism by which FcεRIα expression is maintained remains unknown. In this study, we discovered that a natural antisense transcript,FCER1A-AS, is co-expressed with the sense transcript. The presence ofFCER1A-AS is essential for sense transcript expression in mast cells and basophils, but not for the differentiation of these cells throughcis-regulation. Like FcεRIα knockout mice, mice lackingFCER1A-AS also exhibit reduced survival afterSchistosoma japonicuminfection and a lack of IgE-mediated cutaneous anaphylaxis. Thus, a novel pathway for regulating IgE-mediated allergic diseases through noncoding RNAs has been revealed.