GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE326nnn/GSE326441/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE326441GEOGSEfalseSMD2 reads pseudouridines to regulate mRNA splicing and promote tumorigenesis [RNA-seq]Pseudouridines (Ψ) in mRNA are linked to alternative splicing, but their regulatory mechanisms remain unclear due to the lack of identified reader proteins. Here, we identify SMD2, a core spliceosomal component, as a direct Ψ reader. Using in vitro and ex vivo assays, we show that SMD2 preferentially binds Ψ over unmodified uridines. SMD2 collaborates with PUS family enzymes to regulate alternative splicing by binding Ψ near exon-intron boundaries, modulating the splicing of numerous pre-mRNAs. Notably, the gene encoding SMD2, SNRPD2, is overexpressed across multiple cancers and is essential for tumor cell proliferation through the maturation of key transcripts. These findings uncover a direct mechanistic link between Ψ and spliceosomal function, establishing SMD2 as a critical regulator of Ψ-mediated splicing and a potential cancer therapeutic target.2026/06/17GSE326441GSM9631278GSM9631277GSM9631276GSM9631275GSM9631274GSM9631273GSM9631283GSM9631272GSM9631282GSM9631281GSM9631280GSM963127934284326441Homo sapiens