Mitophagy in pancreatic cancer: mechanistic insights and implications for novel therapeutic strategies

Pancreatic ductal adenocarcinoma (PDAC) presents significant treatment challenges, primarily due to its propensity for developing resistance to therapeutic interventions. While the underlying mechanisms remain elusive, they are closely associated with mitochondrial adaptation in response to treatment. Mitophagy, a selective subtype of autophagy that eliminates damaged or surplus mitochondria, is crucial for tumorigenesis, progression, and treatment resistance in cancers. This review discusses the intricate regulatory pathways of mitophagy in PDAC, focusing on the PINK1/Parkin pathway and receptor-mediated pathways. Furthermore, it explores the therapeutic potential of targeting mitophagy to increase the effectiveness of existing treatments and improve patient survival. Current evidence indicates that combining mitophagy inhibition with conventional chemotherapy yields promising yet inconsistent results, which may be attributed to the context-dependent functions of mitophagy and a lack of specific inhibitors. This review highlights the therapeutic potential of targeting mitophagy in PDAC and underscores the necessity for biomarker-driven patient stratification and the development of pathway-specific modulators in future clinical efforts.