LMT328, a sulfiredoxin inhibitor, induces preferential cancer cell death and tumor regression via oxidative stress

Abstract

Cancer cells are more susceptible to oxidative damage due to their reliance on tightly regulated redox homeostasis. Sulfiredoxin (Srx) is an antioxidant enzyme that restores hyperoxidized peroxiredoxins and contributes to cellular redox regulation. Previously, we demonstrated that pharmacological inhibition of Srx induces preferential death of cancer cells and tumor regression by weakening antioxidant defenses. In this study, we investigated the anticancer efficacy of LMT328, a more potent Srx inhibitor developed through molecular modeling. LMT328 exhibited greater efficacy than the previously reported inhibitor J14 in inhibiting cellular Srx activity, elevating intracellular oxidative stress, inducing mitochondrial damage, and triggering apoptotic cell death in cancer cells. These effects were attenuated by ectopic Srx expression or antioxidant treatment, supporting that LMT328 exerts its cytotoxic effects through oxidative stress resulting from Srx inhibition. Notably, LMT328 induced greater oxidative stress, mitochondrial damage, and cytotoxicity in tumorigenic T80H cells compared with nontumorigenic T80 cells. In a xenograft model, LMT328 significantly suppressed tumor growth with minimal toxicity. Collectively, our findings demonstrate that LMT328 disrupts Srx-dependent redox homeostasis, leading to oxidative stress-associated mitochondrial damage and cancer cell death, and suggest that targeting Srx may represent a promising strategy for redox-based cancer therapy. © 2026 Published by Elsevier Inc.