2. Academic Validation
  3. Liensinine overcomes EGFR-TKI resistance in lung adenocarcinoma through DRP1-mediated autophagy

Liensinine overcomes EGFR-TKI resistance in lung adenocarcinoma through DRP1-mediated autophagy

  • Phytomedicine. 2025 May:140:156593. doi: 10.1016/j.phymed.2025.156593.
Yuling Chen 1,  Chenying Shu 2,  Zhaowei Yan 3,  Saiqun Zhang 1,  Weijie Zhang 1,  Jian Zhao 1,  Anqi Wang 1,  Jianjun Li 1,  Yuanyuan Zeng 4,  Jianjie Zhu 4,  Jian-An Huang 5,  Zeyi Liu 6
Affiliations

Affiliations

  • 1 Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China.
  • 2 Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China; Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
  • 3 Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
  • 4 Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China; Suzhou Key Laboratory for Respiratory Diseases, Suzhou 215006, China.
  • 5 Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China; Suzhou Key Laboratory for Respiratory Diseases, Suzhou 215006, China. Electronic address: huang_jian_an@163.com.
  • 6 Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China; Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, China; Suzhou Key Laboratory for Respiratory Diseases, Suzhou 215006, China. Electronic address: zeyiliu@suda.edu.cn.
PMID: 40054177 DOI: 10.1016/j.phymed.2025.156593
Abstract

Introduction: Persistent upregulation of Autophagy contributes to tumour cells' resistance to EGFR-TKI therapy, and hence, inhibiting Autophagy could be a valuable strategy for overcoming such resistance.

Objectives: This study investigated the effects of liensinine in EGFR-TKI resistant lung adenocarcinoma (LUAD) and to explore the underlying mechanism.

Methods: CCK-8 assay, colony formation, EdU assay and Apoptosis assays were conducted for investigating the effect of EGFR-TKI and liensinine combination treatment in LUAD. Furthermore, autophagic flux were detected by western blot, fluorescence assays and TEM. In addition, by employing a DARTS approach, a CETSA assay, and SPR analysis, we identified DRP1 as a target of liensinine. Finally, by establishing a xenograft model of the disease, the impact of combination treatment in vivo was assessed.

Result: In vitro and in vivo experiments revealed that the novel Autophagy inhibitor liensinine enhanced the sensitivity of LUAD to EGFR-TKIs. This effect was achieved by inhibiting autophagic flux. We then examined whether liensinine inhibits autophagic flux through the impairment of autophagosome and autolysosome degradation. Furthermore, we identified DRP1 as a target of liensinine. The activation of DRP1 by liensinine through dephosphorylation at Ser637 promotes the accumulation of autophagosomes and autolysosomes while simultaneously blocking autophagic flux, thereby enhancing the Cancer cell-killing effects of EGFR-TKIs.

Conclusions: Our study validated the efficacy of liensinine in overcoming EGFR-TKI resistance and elucidated the mechanism underlying liensinine's inhibition of Autophagy.

Keywords

Autophagy; Drug resistance; EGFR-TKI; Liensinine; Lung adenocarcinoma.

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