FOSL1-PRMT1 transcriptional-epigenetic circuit promotes glioblastoma radioresistance via calcyphosine-mediated DNA repair and invasion.

Radioresistance constitutes a major therapeutic barrier in glioblastoma (GBM), frequently leading to tumor recurrence and poor clinical outcomes. Despite advances in multimodal therapies, the molecular mechanisms underlying this resistance remain incompletely understood, limiting the development of effective interventions. This study identifies Fos-like antigen 1 (FOSL1) as a key driver of therapy resistance, with its elevated expression linked to poor prognosis in recurrent GBM. Functionally, FOSL1 knockdown sensitizes GBM cells to irradiation, impairs DNA damage repair, and reduces cell invasiveness. Mechanistically, FOSL1 physically interacts with and stabilizes Protein Arginine Methyltransferase 1 (PRMT1). This interaction enhances PRMT1-mediated asymmetric dimethylation of histone H4 (H4R3me2a) and facilitates methylation of Poly(A) Binding Protein Nuclear 1 (PABPN1). PRMT1, in turn, transcriptionally upregulates Calcyphosine (CAPS), which is essential for the pro-resistance and pro-invasive functions of this axis. We further demonstrate that the FOSL1-PRMT1-CAPS axis concurrently activates both Homologous Recombination (HR) and Non-Homologous End Joining (NHEJ) repair pathways to promote therapeutic resistance. In an orthotopic GBM mouse model, genetic or pharmacological disruption of this axis significantly enhances radiosensitivity and suppresses tumor invasion. Collectively, these findings unveil a previously unrecognized signaling pathway that coordinately regulates DNA repair fidelity and invasive potential in GBM. Our work proposes the FOSL1‑PRMT1‑CAPS axis as a promising therapeutic target for overcoming radioresistance and improving treatment outcomes in GBM patients.