TMSB4Y restrains sphingomyelin synthesis via de novo purine synthesis to exert a tumor suppressor function in male esophageal squamous cell carcinoma.

Y chromosome genes play a vital role in sex difference of cancer. The dysregulation and functional implications of Y chromosome genes in esophageal squamous cell carcinoma (ESCC) remains elusive. Here, we analyze the Y chromosome gene signature and identify TMSB4Y as an emerging prognostic predictor in male ESCC. Functional analyses show that TMSB4Y inhibits the proliferation, invasion and metastasis of male ESCC cells. Mechanistically, we demonstrate that TMSB4Y interacts with PAICS, wherein TMSB4Y disrupts the formation of the PAICS octamer to inhibit purine de novo synthesis, leading to a decrease in the AMP/ATP ratio, subsequently impeding AMPK phosphorylation. Furthermore, we uncover a regulatory cascade orchestrated by the TMSB4Y/PAICS-AMPK axis, which exerts a suppressive effect on sphingomyelin metabolism by inhibiting the expression of sphingomyelin synthases (SMSs). Notably, Malabaricone C, an inhibitor of SMS1 and SMS2, effectively suppresses male ESCC cell proliferation and xenograft tumor growth. Collectively, these findings reveal the regulation of sphingomyelin metabolism by TMSB4Y/PAICS-AMPK axis and underscore the potential of targeting SMSs as a promising therapeutic approach for the treatment of male ESCC.