piR‐RCC Suppresses Renal Cell Carcinoma Progression by Facilitating YBX‐1 Cytoplasm Localization

Abstract PIWI‐interacting RNAs (piRNAs), a novel category of small non‐coding RNAs, are widely expressed in eukaryotes and deregulated in several pathologies, including cancer. Little is known about their function and mechanism in renal cell carcinoma (RCC) progression. Herein, a down‐regulated piRNA in RCC, termed piR‐hsa‐28489 (designated as piR‐RCC), is identified to impede RCC progression both in vivo and in vitro. Mechanistically, piR‐RCC directly interacts with Y‐box binding protein 1 (YBX‐1), thus impeding p‐AKT‐mediated YBX‐1 phosphorylation and its subsequent nuclear translocation. Moreover, YBX‐1 coordinates the transcription of ETS homologous factor (EHF) as a repressor factor. Consequently, piR‐RCC enhances EHF expression, leading to the inhibition of RCC proliferation and metastasis. Based on these, a biomimetic nanoparticle platform is constructed to achieve RCC‐specific targeted delivery of piR‐RCC. The nanoparticles are fabricated using a cell membrane coating derived from cancer cells and used to encapsulate and deliver piR‐RCC plasmids to renal orthotopic implantation in mice, hindering RCC progression. This study illustrates piR‐RCC/YBX‐1/EHF signaling axis in RCC, offering a promising therapeutic avenue for RCC.