Agrimol B inhibits pancreatic ductal adenocarcinoma by induction of lethal mitophagy through decreasing MTERF3

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 CCK-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 (PDO) 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 (MTERF3), promoted the accumulation of 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 MTERF3, hyperactivating PINK1/Parkin-mediated mitophagy, and obstructing autophagic flux. Its synergistic effect with chemotherapy drugs provides experimental evidence supporting its potential clinical translation.