ARNT2-driven transcriptional activation of STRA6 reprograms fatty acid metabolism to promote retroperitoneal liposarcoma progression

Background: Retroperitoneal liposarcoma (RLPS) is a mesenchymal-derived malignant tumor characterized by high aggressiveness and a propensity for local recurrence. Emerging evidence implicates aberrant fatty acid metabolism as a key driver of RLPS progression, yet the transcriptional regulators orchestrating this process remain poorly defined. Methods: Bioinformatics integrating cellular experiments demonstrated the role of fatty acid metabolism in the progression of RLPS. Immunohistochemistry (IHC) and Western blotting (WB) were employed to validate the expression levels of ARNT2, and the role of ARNT2 in tumor progression was demonstrated through CCK8 assays, Transwell invasion assays and wound healing assays. Further experiments confirmed the transcriptional regulatory effect of ARNT2 on STRA6 and demonstrated its control over RLPS progression by modulating intracellular lipid droplet and triglyceride levels. Results: Here, we identify ARNT2 as a novel oncogenic transcription factor that promotes RLPS growth by transcriptionally upregulating STRA6, thereby reprogramming fatty acid metabolism. Specifically, ARNT2 binds to the STRA6 promoter to enhance its activity, thereby upregulating fatty acid metabolic enzymes and promoting lipid droplet accumulation with elevated triglycerides. This metabolic shift fuels energy production and biomass synthesis in RLPS cells, ultimately accelerating tumor proliferation and invasion. Conclusion: This study identifies ARNT2 as a transcriptional modulator of fatty acid metabolism pathways, highlighting its potential as a viable molecular target for RLPS therapy.