Hydroxy stearic acids suppress pancreatic cancer stemness by targeting STAT3 signaling and mitochondrial proteome regulation

Gemcitabine resistance (GR) remains a major clinical challenge in the treatment of pancreatic cancer and often develops within weeks of therapy, largely due to the persistence of cancer stem cells (CSCs). In our previous study, we demonstrated that eicosapentaenoic acid (EPA), a well-known dietary fatty acid with antioxidant and anti-tumor properties, inhibited the growth of KRAS-mutant pancreatic cancer cells by suppressing STAT3 phosphorylation. In this study, we established gemcitabine-resistant murine pancreatic ductal adenocarcinoma (PDAC) cells, designated Panc02-GR, and confirmed that these cells exhibit enhanced tumorigenicity and elevated expression of CSC markers. We investigated the effects of three naturally occurring hydroxy stearic acids (HSAs), commonly found in dairy products, on Panc02-GR cells. These compounds significantly reduced cell viability and downregulated the expression of STAT3, Sox2, and c-Myc at the transcriptional level. Proteomic analysis revealed that HSAs suppressed the expression of mitochondrial proteins associated with Complex I and III of the electron transport chain, the tricarboxylic acid (TCA) cycle, and mitochondrial ribosomal components. Among them, 7-R-hydroxystearic acid (7RHSA) most prominently repressed mitochondrial complex subunit proteins, suggesting that HSAs inhibit pancreatic CSCs by disrupting mitochondrial biogenesis and metabolism. These findings support the potential of hydroxy stearic acids as promising therapeutic agents against gemcitabine-resistant pancreatic cancer.