FDA-approved Dimethyl Fumarate Targets Thioredoxin Reductase to Induce Apoptosis in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is characterized by poor prognosis, which is closely linked to significant tumor heterogeneity and the absence of effective targeted treatments beyond conventional chemotherapy, thereby necessitating the discovery of novel therapeutic options. Altered thioredoxin reductase (TrxR) activity is tightly associated with tumorigenesis and cancer progression, positioning TrxR as a promising target for anticancer intervention. Dimethyl fumarate (DMF), an FDA-approved drug for treatment of psoriasis and multiple sclerosis, has also demonstrated direct antitumor activity in several cancers. Although DMF exhibits significant antitumor effects in TNBC xenograft models, the molecular mechanism underlying its action on TrxR remains to be fully elucidated. Here we show that DMF selectively inhibits TrxR activity by targeting the selenocysteine 498 residue. Pharmacological suppression of TrxR activity by DMF promoted ROS accumulation and disrupted intracellular redox homeostasis, ultimately triggering apoptosis in tumor cells through oxidative stress. Furthermore, the interaction of DMF with GSH may disrupt intracellular thiol balance, thereby reinforcing the apoptotic response elicited in TNBC cells. Interestingly, DMF treatment inhibited tumor growth in vivo. Collectively, these findings identify DMF as a novel TrxR inhibitor that induces redox imbalance and apoptosis in TNBC, highlighting its potential as a repurposed therapeutic agent for this aggressive breast cancer subtype.