Glutathione S-transferase Theta 2 causes drug resistance by inhibiting arsenic trioxide-induced ferroptosis in pancreatic ductal adenocarcinoma.

Chemotherapy remains the cornerstone for the treatment of pancreatic ductal adenocarcinoma (PDAC). However, their efficacy is often undermined by the emergence of drug resistance. Recent evidence has highlighted the critical role of ferroptosis inhibition in mediating this resistance. This study investigates the molecular mechanisms underlying PDAC resistance to arsenic trioxide (ATO), with a particular focus on the role of glutathione S-transferase theta 2 (GSTT2). Both in vivo and in vitro experiments have demonstrated that PDAC cells develop resistance to ATO through the suppression of drug-induced ferroptosis. The inhibition of nuclear factor erythroid 2-related factor 2 (NRF2) failed to restore ferroptosis. Transcriptomic analysis revealed significant upregulation of GSTT2 in ATO-resistant cells, implicating it as a key mediator of resistance. GSTT2 expression was markedly higher in ATO-resistant cells than in ATO-sensitive cells. Silencing GSTT2 enhances the sensitivity of resistant cells to ATO. Mechanistically, GSTT2, a downstream target of NRF2, regulates the expression of glutathione peroxidase 4 (GPX4) and ferritin light chain (FTL). Silencing GSTT2 can enhance drug sensitivity by activating ferroptosis in drug-resistant cells. Our study identifies the NRF2-GSTT2-GPX4 ferroptosis regulatory axis, demonstrating that GSTT2 is a negative regulator of ATO-induced ferroptosis. Targeting this axis may represent a promising therapeutic strategy for overcoming chemotherapy in PDAC.