TRIB3 destabilizes tumor suppressor PPARα expression through ubiquitin- mediated proteasome degradation in acute myeloid leukemia

Aims: Tribbles homolog 3 (TRIB3) is emerging as a multifunctional oncoprotein associated with various cellular events in different tumors. However, the regulatory mechanism of TRIB3 in acute myeloid leukemia (AML) remains unknown. This study aims to investigate the molecular mechanisms and uncover the functions of TRIB3 in AML. Methods: Western blotting and quantitative real-time PCR were used to analyze the expression levels of TRIB3, peroxisome proliferator-activated receptor alpha (PPAR alpha), apoptosis markers and autophagy markers in AML cells. Flow cytometry was used to assess cell apoptosis. The interaction of TRIB3 and PPAR alpha was evaluated by immunofluorescence, coimmunoprecipitation, and in vivo ubiquitination assays. Key findings: We demonstrated that downregulating TRIB3 in leukemic cells effectively induced apoptosis and autophagy by regulating the degradation of PPAR alpha. Mechanistically, TRIB3 interacted with PPAR alpha and contributed to its destabilization by promoting its ubiquitination. When PPAR alpha was activated by its specific agonist clofibrate, the apoptosis and autophagy of AML cells were significantly enhanced. These results were confirmed by rescue experiments. Blocking PPAR alpha expression using the PPAR alpha inhibitor GW6471 reversed the functional influence of TRIB3 on AML cells. Significance: The aim of this study is to provide evidence of the degradation of PPAR alpha by TRIB3 via ubiquitindependent proteasomal degradation. This process meditates the progression of AML and prolongs the survival of leukemic cells. As a result, these data indicate that TRIB3 is a novel and promising therapeutic target for AML treatment.