piR-131582 suppresses lung adenocarcinoma progression by targeting USP22 and inhibiting EMT

Background Piwi-interacting RNAs (piRNAs) are increasingly recognized as important regulators in tumor biology. However, which specific piRNAs actively suppress the progression and metastasis of lung adenocarcinoma (LUAD), and the mechanisms involved, remain largely undefined. This study aimed to identify tumor-suppressive piRNAs in LUAD and clarify their functional regulatory axis. Methods Small RNA sequencing was used to profile piRNA expression in LUAD tissues. Gain-of-function experiments were carried out by overexpressing piR-131582 in A549 and H1299 cell lines. Colony formation assays, flow cytometry, and Transwell assays were performed to evaluate cell proliferation, apoptosis, migration, and invasion, respectively. A mouse xenograft model was utilized to assess in vivo tumor growth. Bioinformatics prediction, combined with rescue experiments, was applied to identify and validate the downstream target of piR-131582. Results We found that piR-131582 was significantly downregulated in LUAD tissues. Overexpression of piR-131582 suppressed colony formation, migration, and invasion in vitro , while promoting apoptosis. In parallel, it notably inhibited the growth of LUAD xenograft tumors in vivo . Mechanistically, piR-131582 directly targeted and degraded USP22. Re-introducing USP22 effectively reversed the anti-tumor effects induced by piR-131582, restoring the epithelial-mesenchymal transition (EMT) phenotype and reactivating EMT-related signaling pathways. Conclusions Our results establish the piR-131582/USP22 axis as a critical tumor-suppressive node in LUAD. Restoring this natural inhibitory pathway may represent a promising direction for future therapeutic investigation in LUAD.