Abstract：
Pancreatic ductal adenocarcinoma (PDAC)/pancreatic cancer, is a highly aggressive malignancy with poor prognosis. Gemcitabine-based chemotherapy remains the cornerstone of PDAC treatment. Nonetheless, the development of resistance to gemcitabine among patients is a major factor contributing to unfavorable prognostic outcomes. The resistance exhibited by tumors is modulated by a constellation of factors such as genetic mutations, tumor microenvironment transforms, environmental contaminants exposure. Currently, comprehension of the relationship between environmental pollutants and tumor drug resistance remains inadequate. Our study found that PFOS/6:2 Cl-PFESA exposure increases resistance to gemcitabine in PDAC. Subsequent in vivo trials confirmed that exposure to PFOS/6:2 Cl-PFESA reduces gemcitabine\'s efficacy in suppressing PDAC, with the inhibition rate decreasing from 79.5 % to 56.7 %/38.7 %, respectively. Integrative multi-omics sequencing and molecular biology analyses have identified the upregulation of ribonucleotide reductase catalytic subunit M1 (RRM1) as a critical factor in gemcitabine resistance. Subsequent research has demonstrated that exposure to PFOS and 6:2 Cl-PFESA results in the upregulation of the RRM1 pathway, consequently enhancing chemotherapy resistance. Remarkably, the influence exerted by 6:2 Cl-PFESA exceeds that of PFOS. Despite 6:2 Cl-PFESA being regarded as a safer substitute for PFOS, its pronounced effect on chemotherapeutic resistance in PDAC necessitates a thorough evaluation of its potential risks related to gastrointestinal toxicity.
摘要：
胰腺导管腺癌（PDAC）/胰腺癌，是一种高度侵袭性的恶性肿瘤，预后差。基于吉西他滨的化疗仍然是PDAC治疗的基石。尽管如此，患者对吉西他滨耐药的发展是导致预后不良的主要因素.肿瘤表现出的耐药性受一系列因素的调节，如基因突变，肿瘤微环境转变，环境污染物暴露。目前,对环境污染物与肿瘤耐药性之间关系的理解仍然不足。我们的研究发现，PFOS/6：2Cl-PFESA暴露会增加PDAC对吉西他滨的耐药性。随后的体内试验证实，暴露于PFOS/6:2Cl-PFESA可降低吉西他滨抑制PDAC的功效，抑制率从79.5%下降到56.7%/38.7%，分别。整合的多组学测序和分子生物学分析已确定核糖核苷酸还原酶催化亚基M1（RRM1）的上调是吉西他滨耐药的关键因素。随后的研究表明，暴露于全氟辛烷磺酸和6:2Cl-PFESA会导致RRM1途径上调，从而增强化疗抗性。值得注意的是,6:2Cl-PFESA的影响超过了PFOS。尽管6:2Cl-PFESA被认为是全氟辛烷磺酸的更安全替代品，其对PDAC化疗耐药的显著影响需要对其与胃肠道毒性相关的潜在风险进行全面评估.
