| First Author | Lee H | Year | 2025 |
| Journal | Mol Metab | Volume | 100 |
| Pages | 102237 | PubMed ID | 40848971 |
| Mgi Jnum | J:371968 | Mgi Id | MGI:8244633 |
| Doi | 10.1016/j.molmet.2025.102237 | Citation | Lee H, et al. (2025) ACAA1 knockout increases the survival rate of KPC mice by activating autophagy. Mol Metab 100:102237 |
| abstractText | OBJECTIVES: We found that the levels of the peroxisomal fatty acid oxidation (FAO) marker in pancreatic ductal adenocarcinoma (PDAC) patients were higher than those in healthy individuals, based on tissue microarray analysis. This study investigates FAO in preclinical in vitro and in vivo models. METHODS: To examine the role of FAO in the peroxisome, we created acetyl-coenzyme A acyltransferase (ACAA1) knockout mice, crossed them with KPC mice, and monitored their survival rates. Additionally, we tested a mouse xenograft model with ACAA1 knockdown in human PDAC cells. RESULTS: In normal cells, ACAA1 knockdown did not affect oxygen consumption. In contrast, in PDAC cells, ACAA1 knockdown reduced the oxygen consumption rate by up to 60% and decreased ATP production by up to 70%. This suggests that peroxisomes in PDAC supply various acyl-carnitines for FAO in mitochondria. In PDAC cells, ACAA1 knockdown lowered ATP levels, resulting in mTOR inactivation and autophagy induction. Additionally, ACAA1 knockdown significantly increased LC3-II levels, leading to growth retardation in mouse xenograft models. Acaa1a(+/-) mice showed a median survival increase of 3 weeks after crossing Acaa1a(+/-) with KPC mice (Kras(G12D/+); Trp53(R172H/+;)Pdx1-Cre, a genetically engineered mice model for PDAC). CONCLUSIONS: ACAA1 knockdown inhibited tumor growth by triggering autophagy, which supported the survival of KPC mice. The most important benefit of targeting ACAA1 is that it blocks tumor growth specifically in cancer cells without harming normal cell energy metabolism. |
