Signaling metabolite succinylacetone activates HIF-1 and promotes angiogenesis in GSTZ1-deficient hepatocellular carcinoma

Aberrant angiogenesis in hepatocellular carcinoma (HCC) is associated with tumor growth, progression, and local or distant metastasis. Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is a transcription factor that plays a major role in regulating angiogenesis during adaptation of tumor cells to nutrient-deprived microenvironments. Genetic defects in Krebs cycle enzymes, such as succinate dehydrogenase and fumarate hydratase, result in elevation of oncometabolites succinate and fumarate, thereby increasing HIF-1 alpha stability and activating the HIF-1 alpha signaling pathway. However, whether other metabolites regulate HIF-1 alpha stability remains unclear. Here, we reported that deficiency of the enzyme in phenylalanine/tyrosine catabolism, glutathione S-transferase zeta 1 (GSTZ1), led to accumulation of succinylacetone, which was structurally similar to alpha-ketoglutarate. Succinylacetone competed with alpha-ketoglutarate for prolyl hydroxylase domain 2 (PHD2) binding and inhibited PHD2 activity, preventing hydroxylation of HIF-1 alpha, thus resulting in its stabilization and consequent expression of vascular endothelial growth factor (VEGF). Our findings suggest that GSTZ1 may serve as an important tumor suppressor owing to its ability to inhibit the HIF-1 alpha/VEGFA axis in HCC. Moreover, we explored the therapeutic potential of HIF-1 alpha inhibitor combined with anti- programmed cell death ligand 1 therapy to effectively prevent HCC angiogenesis and tumorigenesis in Gstz1-knockout mice, suggesting a potentially actionable strategy for HCC treatment.