piR-43452 suppresses bladder cancer progression and enhances gemcitabine sensitivity via GTSF1/PIWIL4-mediated LRP1 mRNA destabilization.

Piwi-interacting RNAs (piRNAs), while crucial for genomic integrity in germline cells, remain poorly characterized in somatic cancers. This study identifies piR-43452 as a significantly downregulated piRNA in bladder cancer (BCa), with loss of expression correlating clinically with muscle invasion and lymph node metastasis. Through assays in vitro and in vivo, we demonstrate that piR-43452 acts as a potent tumor suppressor, inhibiting BCa cell proliferation, migration, and xenograft growth while promoting apoptosis. Mechanistically, we identified that piR-43452 directly binds the 3'UTR of LRP1 mRNA and recruits the GTSF1/PIWIL4 complex, which enhances target cleavage through GTSF1-dependent conformational activation. This post-transcriptional regulation led to significant LRP1 suppression, subsequently inhibiting proliferation and restoring chemosensitivity. Our findings establish a novel piRNA-guided mechanism for overcoming chemoresistance and suggest that targeting the piR-43452/GTSF1/PIWIL4/LRP1 axis may provide therapeutic benefit in gemcitabine-resistant BCa.