2. Academic Validation
  3. Agrimol B inhibits pancreatic ductal adenocarcinoma by induction of lethal mitophagy through decreasing mitochondrial transcription termination factor 3

Agrimol B inhibits pancreatic ductal adenocarcinoma by induction of lethal mitophagy through decreasing mitochondrial transcription termination factor 3

  • Precis Clin Med. 2026 Mar 14;9(2):pbag009. doi: 10.1093/pcmedi/pbag009.
Yifei Ma 1,  Ying Zheng 2,  Ying Zhou 2,  Yang Yang 2,  Jinlu Liu 2,  Ningna Weng 3,  Junhong Han 4,  Qing Zhu 2
Affiliations

Affiliations

  • 1 College of Public Health, Qingdao University, Qingdao 266000, China.
  • 2 Division of Abdominal Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3 Department of Medical Oncology, Fujian Cancer Hospital, Clinical Oncology School of Fujian Medical University, Fuzhou 350011, China.
  • 4 Research Laboratory of Tumor Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
PMID: 41978696 DOI: 10.1093/pcmedi/pbag009
Abstract

Objective: To investigate the inhibitory effect of the natural polyphenol Agrimol B on pancreatic ductal adenocarcinoma (PDAC) and its underlying molecular mechanisms.

Methods: The effects of Agrimol B on PDAC cell proliferation and Apoptosis were assessed using Cell Counting Kit-8, colony formation, and flow cytometry assays. An in vivo PDAC xenograft mouse model was established for evaluation. Label-free quantitative proteomics, western blotting, immunofluorescence, and transmission electron microscopy were employed to analyze mitochondrial function, Autophagy, and related signaling pathways. A patient-derived Organoid model was used to evaluate the synergistic effects of Agrimol B with first-line chemotherapy drugs.

Results: Agrimol B significantly inhibited PDAC growth and induced Apoptosis both in vitro and in vivo. Mechanistically, Agrimol B downregulated the expression of mitochondrial transcription termination factor 3, and promoted the accumulation of PTEN induced kinase 1 (PINK1) in mitochondria and Parkin translocation, thereby excessively activating PINK1/Parkin-dependent Mitophagy. Concurrently, Agrimol B blocked lysosome biogenesis, leading to autophagosome accumulation and impaired autophagic flux. This dysfunctional Autophagy ultimately mediated the anti-PDAC effect of Agrimol B. Furthermore, in PDAC patient-derived organoids, Agrimol B exhibited synergistic effects with first-line chemotherapy drugs such as gemcitabine and nab-paclitaxel.

Conclusion: Agrimol B exerts its anti-PDAC effects by downregulating mitochondrial transcription termination factor 3, hyperactivating PINK1/Parkin-mediated Mitophagy, and obstructing autophagic flux. Its synergistic effect with chemotherapy drugs provides experimental evidence supporting its potential clinical translation.

Keywords

Agrimol B; MTERF3; PINK1/Parkin; mitophagy; pancreatic ductal adenocarcinoma.

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