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

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