Auranofin facilitates gemcitabine sensitivity by regulating TXNRD1-related ferroptosis in pancreatic ductal adenocarcinoma

Gemcitabine-based combination chemotherapy remains the first-line treatment for pancreatic ductal adenocarcinoma (PDAC). However, numerous patients with PDAC develop resistance to gemcitabine, highlighting the need to identify sensitizers or resistance targets. In this study, we constructed a patient-derived xenograft (PDX) model using resected PDAC tissue from patients and established stable gemcitabine-resistant and -sensitive PDX models. RNA sequencing analysis of the gemcitabine-resistant PDX model and cell lines revealed that altered iron ion metabolism significantly affected gemcitabine resistance in PDAC. Gemcitabine-resistant cell lines exhibited altered iron ion levels, which contributed to decreasing lipid peroxidation and ferroptosis. To identify biomarkers of gemcitabine resistance, we established PDX-based machine learning features and found that they may differentiate the effectiveness of chemotherapy and immunotherapy in different patients. TXNRD1 was identified as a potential oncogene that promotes cell migration and proliferation, while inhibiting cell apoptosis. Mechanistically, TXNRD1 knockdown restricted P65 expression and phosphorylation, leading to SLC7A11 depletion and enhanced ferroptosis. This activated ferroptosis, induced by SLC7A11 inhibition, further suppressed gemcitabine resistance in PDAC. Auranofin, a TXNRD1 inhibitor, induced ferroptosis and exerted synergistic effects with gemcitabine in PDAC therapy. Auranofin additionally enhanced the anticancer effects of gemcitabine in a drug-resistant PDAC PDX model. Collectively, TXNRD1 is a potential target for overcoming gemcitabine resistance. Auranofin can inhibit TXNRD1 activation, thereby sensitizing PDAC cells to gemcitabine. Combination therapy with auranofin and gemcitabine may have translational potential for PDAC chemotherapy.