TRIM32-mediated ubiquitination of STING promotes glycolysis and tumor progression.

The Warburg effect, a hallmark of metabolic reprogramming, drives tumor progression, but its upstream regulation remains unclear. Using hepatocellular carcinoma (HCC) as a model, we identify TRIM32, an E3 ubiquitin ligase, as a potent activator of glycolysis that promotes malignancy. TRIM32 is upregulated in HCC tissues and cell lines, correlating with aggressive features and poor prognosis. Gain- and loss-of-function studies show that TRIM32 enhances proliferation, invasion, and migration in vitro and accelerates tumor growth and lung metastasis in xenografts. Mechanistically, TRIM32 mediates K48- and K63-linked polyubiquitination of STING, accelerating its degradation and relieving glycolytic suppression. Reduced STING elevates HK2 and promotes its mitochondrial localization, sustaining glycolysis and bioenergetics. TRIM32 knockdown decreases tumor burden, metastasis, and glycolytic activity, while hepatocyte-targeted STING knockdown rescues tumorigenesis in liver-specific TRIM32 knockout mice. These findings define a TRIM32-STING-HK2 axis that links ubiquitin-mediated suppression of innate immune signaling to glycolytic activation. Although validated in HCC, this mechanism likely applies broadly across solid tumors and nominates TRIM32 as a therapeutic target to reprogram tumor metabolism and limit malignancy.