本研究旨在评估癌细胞外泌体对胰腺癌（PC）化疗耐药性预测的潜力，并通过RNA测序和质谱技术探索分子机制。我们试图了解外泌体介导的中链酰基辅酶脱氢酶（ACADM）水平与体内和PC患者对吉西他滨反应之间的关系。我们采用功能丧失、功能增强、代谢组质谱和异种移植瘤模型来研究外泌体ACADM对PC化疗耐药性的影响。我们的结果显示，与吉西他滨敏感性不同的PC细胞之间的外泌体中涉及脂质代谢的分子存在差异。体外外泌体ACADM（外泌体-ACADM）与体内吉西他滨敏感性呈强相关，可用作胰腺癌患者术后吉西他滨化疗敏感性的预测指标。此外，发现ACADM通过影响谷胱甘肽过氧化物酶4（GPX4）和甲羟戊酸途径，调节吉西他滨的反应。还观察到ACADM增加了不饱和脂肪酸的消耗并降低了细胞内脂质过氧化物和活性氧（ROS）水平。总之，本研究表明外泌体-ACADM可能是预测患者化疗响应性的可行生物标志物。© 2023. BioMed Central Ltd., part of Springer Nature.

This study aimed to evaluate the potential of exosomes from cancer cells to predict chemoresistance in pancreatic cancer (PC) and explore the molecular mechanisms through RNA-sequencing and mass spectrometry. We sought to understand the connection between the exosomal Medium-chain acyl-CoA dehydrogenase (ACADM) level and the reaction to gemcitabine in vivo and in patients with PC. We employed loss-of-function, gain-of-function, metabolome mass spectrometry, and xenograft models to investigate the effect of exosomal ACADM in chemoresistance in PC. Our results showed that the molecules involved in lipid metabolism in exosomes vary between PC cells with different gemcitabine sensitivity. Exosomal ACADM (Exo-ACADM) was strongly correlated with gemcitabine sensitivity in vivo, which can be used as a predictor for postoperative gemcitabine chemosensitivity in pancreatic patients. Moreover, ACADM was found to regulate the gemcitabine response by affecting ferroptosis through Glutathione peroxidase 4 (GPX4) and mevalonate pathways. It was also observed that ACADM increased the consumption of unsaturated fatty acids and decreased intracellular lipid peroxides and reactive oxygen species (ROS) levels. In conclusion, this research suggests that Exo-ACADM may be a viable biomarker for predicting the responsiveness of patients to chemotherapy.© 2023. BioMed Central Ltd., part of Springer Nature.