Metabolic reprogramming, particularly the dysregulation of cholesterol metabolism, is a hallmark of pancreatic ductal adenocarcinoma (PDAC). However, the underlying molecular drivers remain largely elusive. In this study, we demonstrate that Tribbles homolog 1 (TRIB1) is elevated in PDAC tissues and is significantly associated with poor prognosis. Functionally, TRIB1 mRNA knockdown suppresses PDAC cell growth and tumor formation, while its overexpression promotes both. Mechanistically, TRIB1 protein binds to the DNA-binding domain of PPARγ and inhibits its transcriptional activity. This interaction relieves the PPARγ-mediated repression of HMGCR, the rate-limiting enzyme in the mevalonate pathway, thereby fueling de novo cholesterol biosynthesis. Furthermore, in vivo experiments indicate that PDAC tumors with high TRIB1 expression were more sensitive to the HMGCR inhibitor atorvastatin. Collectively, our findings highlight the critical role of the TRIB1-PPARγ-HMGCR axis in the metabolic rewiring of PDAC and suggest that TRIB1 may serve as a predictive biomarker for optimizing statin-based metabolic therapies.
Sun et al. (Sun,) studied this question.