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

Currently, chemotherapy remains a key treatment modality for pancreatic ductal adenocarcinoma (PDAC). However, the emergence of drug resistance limits the chemotherapeutic efficacy. Ferroptosis inhibition plays a significant role in chemotherapy resistance. This study investigates the potential mechanisms of PDAC resistance to arsenic trioxide (ATO) and explores the role of GSTT2 in chemotherapeutic resistance. PDAC cells showed ATO resistance due to inhibition of drug-induced ferroptosis, which was validated in vivo and in vitro. Inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) did not restore ferroptosis. Transcriptomic analysis showed that GSTT2 is significantly upregulated in ATO-resistant cells, suggesting it is a key factor in drug resistance. GSTT2 is highly expressed in ATO-resistant cells compared to ATO-sensitive cells. Silencing GSTT2 enhances the sensitivity of resistant cells to ATO. Further studies indicate that 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. The development of therapeutic strategies targeting the Nrf2-GSTT2-GPX4 axis will open new avenues for combating resistance to chemotherapy in PDAC.