Targeting thioredoxin reductase by ibrutinib promotes apoptosis of SMMC-7721 cells.

Ibrutinib (IBT), the first-in-class inhibitor of Bruton's tyrosine kinase (BTK), has demonstrated clinical activity against various B-cell malignancies. IBT is the second agent approved by U.S. Food and Drug Administration via Breakthrough Therapy Designation. Aside from its therapeutic mechanism through BTK inhibition, IBT has other target sites reported for cancer therapy, leading us to investigate whether IBT has unreported targets. Our study revealed that IBT can inhibit the growth of SMMC-7721 cells through irreversible inhibition of mammalian thioredoxin reductase (TrxR) enzymes, which are components of the thioredoxin (Trx) system. Further study demonstrated that IBT can cause cellular ROS elevation and induce oxidative stress-mediated apoptosis. The discovery of a new target of IBT sheds light on better understanding its anticancer mechanisms and provides a theoretical foundation for its further use in clinical therapy.