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Qiang Wang, Qiyao Nong, Junguo Zang, Meiyu Gao, Ying Zhang, Xinyuan Hao, Yuan Tian, Fengguo Xu, Pei Zhang. PFKM promotes chemoresistance in lung adenocarcinoma by regulating RAB8B mediated exosome release[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101450
Citation: Qiang Wang, Qiyao Nong, Junguo Zang, Meiyu Gao, Ying Zhang, Xinyuan Hao, Yuan Tian, Fengguo Xu, Pei Zhang. PFKM promotes chemoresistance in lung adenocarcinoma by regulating RAB8B mediated exosome release[J]. Journal of Pharmaceutical Analysis. doi: 10.1016/j.jpha.2025.101450

PFKM promotes chemoresistance in lung adenocarcinoma by regulating RAB8B mediated exosome release

doi: 10.1016/j.jpha.2025.101450
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This study was supported by the National Natural Science Foundation of China (Grant Nos.: 82104117, 82473883, and U24A20788), the Fundamental Research Funds for the Central Universities (Grant No.: 2632024ZD02), and Project Program of State Key Laboratory of Natural Medicines (China Pharmaceutical University, Grant No.: SKLNMZZ2024JS21).

  • Received Date: Feb. 17, 2025
  • Accepted Date: Sep. 12, 2025
  • Rev Recd Date: Sep. 09, 2025
  • Available Online: Sep. 13, 2025
  • Lung adenocarcinoma (LUAD), the most widely existing subtype of non-small cell lung cancer (NSCLC), is a leading cause of cancer-related mortality, characterized by challenging early diagnosis, high rates of recurrence and metastasis, and poor prognosis. Chemotherapy remains the primary treatment for advanced LUAD, but its effectiveness is often hindered by the development of chemoresistance. In this study, a targeted metabolomics method unveiled a marked up-regulation of glycolysis in chemotherapy-resistant LUAD cells. Particularly, the ratio of fructose 1,6-bisphosphate (FBP) to fructose 6-phosphate (F6P) reflected the activity of the rate-limiting enzyme Phosphofructokinase muscle isoform (PFKM) was significantly elevated. We further observed a significant increase in exosome release in chemotherapy-resistant cells. More importantly, it was found that the interaction between PFKM and exosomes plays a role in regulating chemoresistance in LUAD. Mechanistically, PFKM influences exosomes release by modulating Ras-related protein Rab-8B (RAB8B) expression, impacting apoptosis and glycolytic metabolism, thereby promoting chemoresistance. Furthermore, drug-resistant cells enhance chemoresistance in sensitive cells by releasing exosomes with heightened glycolytic activity. These findings highlight the crucial role of the PFKM-RAB8B axis in promoting chemoresistance, suggesting it as a potential therapeutic target for countering LUAD chemoresistance.
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