Overall, the aim of this study was to reveal the critical role of EPHB1 in PRAD progression, and it was found that it activates SMAD3 phosphorylation through interactions with GSK3B to promote tumor cell survival, invasion, and the formation of an immunosuppressive microenvironment, which provides new evidence and perspectives on the progression mechanism of PRAD. This evidence concerns the gene EPHB1 and prostate adenocarcinoma.