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
  • 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: [email protected].
  • 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: [email protected].
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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