Sulforaphane potentiates the efficacy of chemoradiotherapy in glioblastoma by selectively targeting thioredoxin reductase 1.

Chemoradiotherapy is a conventional treatment modality for patients with glioblastoma (GBM). However, the efficacy of this approach is significantly hindered by the development of therapeutic resistance. The thioredoxin system, which plays a crucial role in maintaining redox homeostasis, confers protection to cancer cells against apoptosis induced by chemoradiotherapy. Herein, we demonstrate that sulforaphane (SFN), an isothiocyanate phytochemical with anti-cancer effects, inhibits the activity of thioredoxin reductase 1 (TrxR1) through covalent conjugation with residues C59/64/497&U498. This inhibition of TrxR1 leads to the accumulation of reactive oxygen species (ROS), thereby enhancing chemoradiotherapy-induced apoptosis in GBM cells. Furthermore, SFN-induced ROS accumulation facilitates the polarization of M1-like macrophages, which synergistically sensitize GBM tumors to chemoradiotherapy. In conclusion, our study unveils that SFN has potential benefits in improving the effect of chemoradiotherapy and prognosis for GBM patients by targeting TrxR1.