Uncovering MYOF as a novel therapeutic target in glioblastoma: mechanistic insights and drug discovery.

Abstract

Glioblastoma (GBM) is the most common type of primary malignant brain tumor, characterized by a poor prognosis, high recurrence rate, and elevated mortality. In recent years, gene-targeted therapies leveraging small molecule compounds have gained momentum as a promising avenue for GBM intervention. Myoferlin (MYOF), a type II membrane protein of the Ferlin family, has emerged as a key regulator of membrane dynamics-governing processes such as vesicular trafficking, endocytosis, and membrane repair. In this study, we explore the previously uncharted role of MYOF in GBM progression and its potential as a diagnostic and therapeutic target. Our data reveal that silencing MYOF markedly suppresses glioma growth both in vitro and in vivo. Mechanistically, MYOF knockdown disrupts the nuclear translocation of phosphorylated STAT3 (P-STAT3), a critical oncogenic signaling event. Notably, we identified Entacapone (ENT), a small molecule capable of targeting MYOF, which significantly impedes glioma development across experimental models. These findings position MYOF as a novel molecular lever in GBM pathogenesis and highlight ENT as a potential therapeutic agent that exerts anti-glioma effects by blocking MYOF-mediated P-STAT3 nuclear import. The diagram illustrates a novel regulatory mechanism of IL-6/STAT3 signaling involving MYOF. Upon IL-6 stimulation, STAT3 undergoes phosphorylation. MYOF then binds to phosphorylated STAT3 and facilitates its translocation into the nucleus to regulate target gene expression. The compound ENT acts as a targeted inhibitor of this process by binding to MYOF, thereby blocking the nuclear transport of phosphorylated STAT3 and suppressing downstream signaling.