PiR-26681: A Promising Therapeutic Inhibitor Targeting METTL3/METTL14 Complex-Mediated FBXO16 M6A Modification and Suppressing the EMT/WNT Pathway in Ovarian Cancer

Abstract Ovarian cancer (OV), a prevalent gynecological malignancy, is characterized by poor outcomes and limited treatment options. Compared to patients with early stages of the disease, patients with advanced ovarian cancer have significantly lower survival rates. For these reasons, investigating a nucleic acid that may be a promising treatment for ovarian cancer was the main goal of this study, particularly in terms of preventing the disease from progressing from its primary stage to an advanced one. Significantly, individuals with ovarian cancer displayed a diminished amount of piR-26681, particularly in the later stages of the disease. Moreover, piR-26681 is associated with a favorable prognosis. Overexpression of piR-26681 in ovarian cancer cells significantly inhibited malignant behaviors. Mechanistically, piR-26681 interacted with METTL3 and METTL14, enhancing their stability and facilitating their binding. It also elevated the levels of m6A methylation and enhanced the stability of METTL14 and FBXO16 mRNAs. Consequently, this led to downregulation of β-catenin and suppression of the WNT and EMT signaling pathways. In vivo, experiments using xenograft models and patient-derived organoids (PDOs) further confirmed the tumor-suppressive effects of piR-26681. These findings indicate that piR-26681 represents a potentially promising strategy for improving the treatment outcomes of ovarian cancer.