Abstract
Hepatocellular carcinoma (HCC) is an aggressive cancer with limited therapeutic targets and a poor prognosis. Aberrant energy metabolism plays a pivotal role in HCC progression by fulfilling the energy demands of rapidly proliferating tumor cells. In this study, tripartite motif-containing protein 47 (TRIM47) was found to be significantly upregulated in patient-derived HCC tissues, with clinical data revealing that higher TRIM47 expression correlates with poorer patient outcomes. Mechanistic investigations demonstrated that TRIM47 remodels energy metabolism by glycolytic reprogramming through its interaction with the K51 site of fructose-1,6-bisphosphatase (FBP1) through K48-linked ubiquitination, thereby promoting HCC proliferation and tumor metastasis. Rescue experiments and bortezomib intervention experiments further confirmed that FBP1 is essential for mediating the oncogenic effects of TRIM47 in HCC progression. To explore its therapeutic potential, TRIM47 siRNA was developed and loaded into poly (lactic acid)-DC-Chol nanoparticles (siTRIM47@PD NPs), which significantly reduced tumor growth and metastasis in an orthotopic HCC animal model, highlighting the potential of TRIM47 as a therapeutic target. Together, these findings underscore the pivotal role of TRIM47 in HCC progression through FBP1-mediated regulation of energy metabolism, and highlight siRNA-based TRIM47 targeting as a promising approach to improve HCC treatment outcomes.