PIWIL1 activates the R2TP-TELO2-mTORC1 axis independently of piRNA to promote TOP mRNA translation in gastric cancer.

PIWI proteins, a subfamily of the PAZ-PIWI domain (PPD) protein family, are traditionally regarded as germline factors that partner with PIWI-interacting RNAs (piRNAs) to silence transposons and regulate gene expression. However, growing evidence implicates PIWI proteins as oncogenic drivers in diverse somatic cancers, often acting through piRNA-independent mechanisms that remain incompletely understood. Here, we integrate transcriptomic, translatomic, and proteomic profiling of wild-type versus PIWIL1-knockout gastric cancer cells to uncover a non-canonical, translational role for PIWIL1, one of the four human PIWI proteins. We find that PIWIL1 selectively enhances the translation of 5'-terminal oligopyrimidine (TOP) mRNAs by activating mTOR complex 1 (mTORC1). Mechanistically, PIWIL1 interacts with the R2TP chaperone complex (RUVBL1-RUVBL2-RPAP3-PIH1D1) and promotes its association with TELO2, facilitating mTOR-RAPTOR assembly and mTORC1 activation. Functionally, PIWIL1 deficiency sensitizes gastric cancer cells to mTOR inhibition, and in clinical samples, PIWIL1 expression positively correlates with mTORC1 pathway activity. Together, these findings define a novel piRNA-independent mechanism through which PIWIL1 contributes to tumor progression, extend PIWI-mediated translational control from the germline to human cancers, and establish PIWIL1 as a potential therapeutic target for gastric cancer in synergy with mTOR inhibition.