Data Sheet 1_A dual inhibitor of TrxR1 and XIAP induces pyroptosis in melanoma.docx

Malignant melanoma ranks among the most aggressive forms of cancer, with high rates of metastasis and recurrence, as well as a poor prognosis. Consequently, an urgent need is to develop novel precision therapeutic strategies and corresponding drugs. Previous studies have shown that both X-linked inhibitor of apoptosis (XIAP) and thioredoxin reductase 1 (TrxR1) participate in the resistance of melanoma to chemotherapy-induced cell death. In this study, we designed and synthesized a series of derivatives of natural compounds derived from Toona sinensis to simultaneously inhibit TrxR1 activity and destabilize the XIAP protein. The new dual-target inhibitor TRI-03 has significant antiproliferative effects on melanoma cells. Mechanistically, TRI-03 not only increases intracellular reactive oxygen species (ROS) levels by inhibiting TrxR1 activity but also decreases XIAP expression, leading to the activation of the caspase-9/caspase-3/GSDME axis and irreversible GSDME-mediated pyroptosis in melanoma cells. Our in vivo animal study confirmed that TRI-03 effectively inhibits melanoma proliferation and metastasis without severe side effects. Therefore, our study identified TRI-03 as a potential antitumor candidate for future development to address melanoma.