Abstract: Neurogenesis in the mammalian olfactory epithelium is a continuous process. Our previous study showed that transmembrane protein 59 (Tmem59) is a critical regulator of epithelial homeostasis, while its deficiency leads to impaired proliferation, loss of sensory neurons, and inflammatory activation; however, the underlying mechanism has not been clarified. In the current study, single-cell RNA-sequencing data were analyzed, revealing that Tmem59 deficiency induces a senescent state in olfactory epithelial cells and the differential expression of aging-related genes as well as genes associated with nasal diseases in basal cells and sensory neurons. The intercellular communications between globose basal cells and sensory neurons were enhanced, while the target genes in sensory neurons were associated with cell growth and differentiation. Along the differentiation trajectory, upregulated genes in Tmem59-/- mOSNs were associated with macroautophagy, such as Ambra1 and Prkn. Tmem59 deficiency was shown to impair cell proliferation and neuronal generation and enhance cell apoptosis in the OE. We also identified several transcriptional network hubs in immune cells, and the target genes to these hubs in Tmem59-/- cells were associated with several critical signaling pathways such as chemokine and Rap1. Finally, Tmem59-/- organoids exhibited a differential expression of genes related with nasal diseases. Collectively, Tmem59 deficiency leads to a series of abnormities at the transcriptional level such as senescent features and an aberrant neuronal differentiation trajectory, potentially putting forward important targets for the treatment of nasal diseases.