Neferine‐Targeted Inhibition of TrxR1 Triggers Apoptosis Through Disrupting Redox Homeostasis in Pancreatic Cancer Cells

Overactivation of thioredoxin reductase 1 (TrxR1) is implicated in tumor development. This study aims to elucidate the efficacy and mechanisms by which neferine (Nef) exerts its anti‐tumor effects in pancreatic cancer through targeting TrxR1. The results demonstrate that Nef directly binds to and inhibits the enzymatic activity of TrxR1, leading to an abnormal accumulation of reactive oxygen species (ROS) in mitochondria. This accumulation subsequently results in a decrease in mitochondrial membrane potential, DNA damage, and the activation of apoptotic pathways, characterized by changes in the Bax/Bcl‐2 ratio and a cascade reaction involving caspases. Reversal experiments indicated that the ROS scavenger NAC significantly counteracted the inhibitory effects of Nef on pancreatic cancer cell proliferation and its induction of apoptosis. Genetic experiments confirmed that the knockdown of TrxR1 enhances the anti‐pancreatic cancer effects of Nef. Furthermore, a nude mouse xenograft tumor model validated the in vivo efficacy of Nef in suppressing tumor growth via TrxR1 inhibition. Bioinformatic analysis suggested that elevated TrxR1 expression is associated with a poor prognosis in pancreatic cancer. Collectively, our results confirm that Nef is a novel inhibitor of TrxR1 and provide experimental evidence for a therapeutic strategy targeting TrxR1.