Antitumor Activity of a Synthetic Small RNA Based on a Maytenus hookeri Sequence in Non-Small Cell Lung Cancer

Lung cancer remains the leading cause of cancer-related mortality worldwide, highlighting the urgent need for novel therapeutic strategies. This study aimed to identify bioactive small RNAs derived from Maytenus hookeri Loes. and evaluate their anti-tumor potential against non-small cell lung cancer (NSCLC). The 50 most abundant small RNAs were synthesized and screened in NCI-H460 cells using the MTS assay. Among them, MDM-sRNA-39 significantly inhibited cell viability and was selected for further evaluation of its anti-tumor activity. It reduced the percentage of cells that traversed the Transwell membrane and promoted apoptosis in NCI-H460 cells. Bioinformatics prediction suggested KRAS as a potential target of MDM-sRNA-39, and KRAS was among the targets experimentally validated by dual-luciferase reporter assays, RT-qPCR, and Western blot, showing that MDM-sRNA-39 suppresses KRAS expression at both mRNA and protein levels. In vivo, MDM-sRNA-39 was orally administered as a bencaosome in a Kras^LSL-G12D/p53^LoxP/LoxP autochthonous lung cancer mouse model. Tumor burden was reduced and cleaved caspase-3 staining was increased in the mouse model. Collectively, these findings identify MDM-sRNA-39, a synthetic small RNA based on a sequence identified from Maytenus hookeri Loes., as a candidate with anti-tumor activity, supporting the potential strategy for developing RNA-based therapeutics from traditional Chinese medicine.