Low-dose TNF-α drives malignant progression and lipid metabolism in glioblastoma through the TRAF2–FASN axis [RNA-Seq TRAF2-KD]

Lipid metabolism plays a critical role in the progression of cancers, including glioblastoma (GBM). Tumor necrosis factor-α (TNF-α) exhibits a dual role in the tumor microenvironment: at high concentrations, it induces cell death and exerts anti-tumor effects, while at low doses, it demonstrates pro-tumorigenic activity. This study investigates the regulatory effects of low-dose TNF-α on the malignant behavior and lipid metabolism of GBM. The results show that low-dose TNF-α (10 ng/mL) significantly promotes GBM cell Malignant phenotypes and lipid droplet accumulation via the TNFR signaling pathway, a process dependent on its downstream adaptor protein, Tumor necrosis factor receptor-associated factor 2 (TRAF2). Mechanistically, TRAF2 interacts with Fatty acid synthase (FASN) through its TRAF domain and, serving as an E3 ubiquitin ligase, leverages its RING domain to mediate K63-linked polyubiquitination of FASN. This enhances FASN protein stability, promotes lipid synthesis, and ultimately drives tumor progression. Furthermore, through virtual screening, the small-molecule compound Jionoside B1 was identified to target the RING domain of TRAF2, effectively inhibiting K63-linked ubiquitination of FASN and disrupting the TRAF2–FASN interaction and protein accumulation. In both in vitro and in vivo experiments, Jionoside B1 significantly suppressed lipid synthesis and attenuated tumor growth. This study systematically elucidates the mechanism by which low-dose TNF-α regulates lipid metabolism and promotes GBM malignant progression via the TRAF2–FASN axis, providing not only new insights into the "double-edged sword" role of TNF-α in the tumor microenvironment but also a potential novel therapeutic strategy for targeting this pathway in GBM treatment.