2. Academic Validation
  3. Gymconopin C exhibits anti-non-small cell lung cancer effect by regulating miR-6777-5p/ADRB2 pathway to promote mitophagy

Gymconopin C exhibits anti-non-small cell lung cancer effect by regulating miR-6777-5p/ADRB2 pathway to promote mitophagy

  • J Adv Res. 2025 Dec 19:S2090-1232(25)01014-8. doi: 10.1016/j.jare.2025.12.023.
Xue Li 1,  Mingyu Han 2,  Limei Zhang 2,  Xiaofang Xie 3,  Chenying Li 4,  Heng Zhang 2,  Junsha An 2,  Jianning Yang 2,  Shuang Pu 2,  Yue Duan 2,  Changnian Yang 5,  Cheng Peng 6,  Hailin Tang 7,  Fu Peng 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China; Key Laboratory of Standardization of Chinese Medicine (Chengdu University of Traditional Chinese Medicine), Ministry of Education, Chengdu 611137, China.
  • 2 Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
  • 3 Key Laboratory of Standardization of Chinese Medicine (Chengdu University of Traditional Chinese Medicine), Ministry of Education, Chengdu 611137, China.
  • 4 School of Obstetrics and Pediatrics, Guangdong Medical University, Zhanjiang, China.
  • 5 The First Clinical College, Guangdong Medical University, Zhanjiang, China; Medical Research Institute, Guangdong Provincial People's Hospital, Guangzhou, China. Electronic address: [email protected].
  • 6 Key Laboratory of Standardization of Chinese Medicine (Chengdu University of Traditional Chinese Medicine), Ministry of Education, Chengdu 611137, China. Electronic address: [email protected].
  • 7 State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 8 Department of Pharmacology, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: [email protected].
PMID: 41423048 DOI: 10.1016/j.jare.2025.12.023
Abstract

Introduction: Non-small cell lung Cancer (NSCLC) remains the leading cause of morbidity and mortality from malignant tumors in China with therapeutic limitations. Developing novel therapeutic agents and innovative treatment strategies is critical for advancing NSCLC management. Gymconopin C, a compound isolated from Bletilla striata, has demonstrated potential anti-NSCLC activity; However, the underlying mechanism remains elusive.

Objectives: This study aimed to decipher the anti-NSCLC mechanism of Gymconopin C by demonstrating its induction of PINK1/Parkin-mediated Mitophagy via the miR-6777-5p/ADRB2 pathway, and to establish the fundamental regulatory role of miRNA/mRNA axis in NSCLC suppression. This study establishes a novel therapeutically targetable pathway and offers a mechanistically grounded candidate for NSCLC therapy.

Methods: Integrated in vitro and in vivo strategies were used to elucidate the anti-NSCLC mechanism of Gymconopin C. Inhibitory effects on two NSCLC cell lines were assessed using CCK-8 proliferation, transwell migration and invasion assays. Subsequently, transmission electron microscopy and mitochondrial functional analyses were conducted to assess Mitophagy. Transcriptomic profiling revealed dysregulation of the miR-6777-5p/ADRB2 axis, and gain/loss-of-function experiments were performed to investigate its functional role in Mitophagy. Finally, the therapeutic efficacy and pathway modulation were evaluated in vivo using zebrafish xenograft and murine ectopic tumor models.

Results: Gymconopin C significantly inhibited the proliferation, migration and invasion of NSCLC cells; induced cell cycle arrest and enhanced Apoptosis of A549 cells. Mechanistically, it modulated the miR-6777/ADRB2 axis to promote PINK/Parkin-mediated Mitophagy, ultimately leading to NSCLC growth arrest in both in vivo and in vitro experiments.

Conclusion: Gymconopin C exerts tumor-suppressive effects by activating PINK1/Parkin-mediated Mitophagy via the miR-6777-5p/ADRB2 axis, highlighting its potential as a therapeutic agent for NSCLC.

Keywords

Gymconopin C; Mitophagy; Non-small cell lung cancer; Zebrafish xenograft and murine ectopic tumor models; miR-6777-5p/ADRB2 axis.

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