IRF1 Inhibits Therapy-Induced Senescence of Glioblastoma Cells Through OAS2.

Glioblastoma (GBM), a highly aggressive brain tumor, is characterized by poor treatment outcomes and a strong tendency to recur after therapy. Therapy-induced senescence (TIS) of GBM cells has emerged as a key driver of GBM progression and relapse. Temozolomide (TMZ), which serves as the standard chemotherapeutic agent for GBM, is known to induce senescence; however, the molecular mechanisms underlying this process remain largely unknown. In this work, we found that interferon regulatory factor-1 (IRF1) was downregulated in TMZ-induced senescent GBM cells. Functionally, knockdown of IRF1 increased the activity of senescence-associated β-galactosidase (SA-β-gal), reduced protein expression of Lamin B1, inhibited cell division, and enhanced senescence-associated secretory phenotype (SASP) of GBM cells, indicating that downregulation of IRF1 promotes senescence of GBM cells. Conversely, overexpression of IRF1 partially reversed TMZ-induced senescence. Further exploration revealed that downregulation of IRF1 reduced the expression of 2',5'-oligoadenylate synthetase 2 (OAS2), and overexpression of IRF1 increased the expression of OAS2. OAS2 was also downregulated in TMZ-induced senescent GBM cells, and knockdown of OAS2 induced senescence of GBM cells as well. Taken together, our study reveals that IRF1 inhibits TMZ-induced senescence of GBM cells through OAS2, highlighting a novel regulatory axis that may offer potential therapeutic targets for improving GBM treatment.