Inhibition of FOS‐Like Antigen 1 Reduces Chemoresistance to Temozolomide Through Stemness Reprogramming via IL‐6/STAT3 Tyr705 Pathway

ABSTRACT Glioblastoma (GBM) is the most lethal brain tumor, characterized by strong resistance to conventional therapies. Despite recent therapeutic advancements, overcoming chemoresistance remains a major challenge. Here, we identified FOS‐like antigen 1 (FOSL1) as a novel therapeutic target in GBM, particularly in patients with resistance to conventional drugs, including temozolomide (TMZ). FOSL1 gene was identified from the DepMap database as a potential mediator of TMZ resistance in GBM and found to be associated with chemoresistance molecular signatures and poor clinical outcomes. Functional analyses in GBM cells revealed that FOSL1 suppression enhanced apoptosis, induced G0/G1 cell cycle arrest, and reduced both cell migration and stemness marker expression. Transcriptomic profiling, including single‐cell RNA‐seq and bulk RNA‐seq, highlighted the pivotal role of the interleukin‐6 (IL‐6)/STAT3 signaling pathway in FOSL1‐mediated stemness. Mechanistically, in vitro experiments demonstrated that FOSL1 induces GBM stemness through IL‐6‐pSTAT3 Tyr705 signaling axis. Furthermore, vemurafenib, which targets FOSL1, was identified as a potential therapeutic agent against TMZ‐resistant GBM in a mouse model. These findings suggest that FOSL1 promotes TMZ chemoresistance by regulating IL‐6‐pSTAT3 Tyr705 ‐mediated stemness in GBM cells, making it a promising therapeutic target to overcome chemoresistance in GBM.