Chen Rong, Chen Kaidi, Zhan Xiaofeng, Qi Yuwei, Wang Hangjie, Shen Lingshuang, Xue Shuai, Chen Junyan, Chen Liping, Sheng Yuxin, Dai Lewei, Wang An, Wang Hong, Xiong Yang, Cheng Guilin, Mu Chaofeng, Gu Mancang, Li Wei
School of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, PR China.
Pharmacy Department, Fuyang TCM Hospital of Orthopedics Affiliated to Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, PR China.
Free Radic Biol Med. 2025 Oct;238:402-416. doi: 10.1016/j.freeradbiomed.2025.06.053. Epub 2025 Jul 1.
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.
化疗仍然是胰腺导管腺癌（PDAC）治疗的基石。然而，耐药性的出现常常削弱了它们的疗效。最近的证据强调了铁死亡抑制在介导这种耐药性中的关键作用。本研究调查了PDAC对三氧化二砷（ATO）耐药的分子机制，特别关注谷胱甘肽S-转移酶θ2（GSTT2）的作用。体内和体外实验均表明，PDAC细胞通过抑制药物诱导的铁死亡而对ATO产生耐药性。抑制核因子红细胞2相关因子2（NRF2）未能恢复铁死亡。转录组分析显示，ATO耐药细胞中GSTT2显著上调，表明它是耐药的关键介导因子。ATO耐药细胞中GSTT2的表达明显高于ATO敏感细胞。沉默GSTT2可增强耐药细胞对ATO的敏感性。从机制上讲，GSTT2作为NRF2的下游靶点，调节谷胱甘肽过氧化物酶4（GPX4）和铁蛋白轻链（FTL）的表达。沉默GSTT2可通过激活耐药细胞中的铁死亡来增强药物敏感性。我们的研究确定了NRF2-GSTT2-GPX4铁死亡调节轴，表明GSTT2是ATO诱导的铁死亡的负调节因子。靶向该轴可能是克服PDAC化疗耐药的一种有前景的治疗策略。
