肝细胞癌 (HCC) 中的异常血管生成与肿瘤生长、进展以及局部或远处转移相关。缺氧诱导因子 1α (HIF-1α) 是一种转录因子，在肿瘤细胞适应营养匮乏的微环境过程中在调节血管生成中发挥重要作用。三羧酸循环酶（例如琥珀酸脱氢酶和富马酸水合酶）的遗传缺陷会导致致癌代谢物琥珀酸和富马酸升高，从而增加 HIF-1α 稳定性并激活 HIF-1α 信号通路。然而，其他代谢物是否调节 HIF-1α 稳定性仍不清楚。在这里，我们报道了苯丙氨酸/酪氨酸分解代谢中的酶谷胱甘肽S-转移酶zeta 1 (GSTZ1)缺陷导致琥珀酰丙酮的积累，其结构与α-酮戊二酸相似。琥珀酰丙酮与 α-酮戊二酸竞争 PHD2 结合并抑制 PHD2 活性，防止 HIF-1α 羟基化，从而使其稳定并随后表达血管内皮生长因子 (VEGF)。我们的研究结果表明，GSTZ1 可能作为一种重要的肿瘤抑制因子，因为它能够抑制 HCC 中的 HIF-1α/VEGFA 轴。此外，我们探索了 HIF-1α 抑制剂联合抗 PD-L1 疗法在 Gstz1 敲除小鼠中有效预防 HCC 血管生成和肿瘤发生的治疗潜力，这为 HCC 治疗提出了一种潜在可行的策略。

Aberrant angiogenesis in hepatocellular carcinoma (HCC) is associated with tumor growth, progression, and local or distant metastasis. Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that plays a major role in regulating angiogenesis during adaptation of tumor cells to nutrient-deprived microenvironment. Genetic defects in Krebs cycle enzymes, such as succinate dehydrogenase and fumarate hydratase, result in elevation of oncometabolites succinate and fumarate, thereby increasing HIF-1α stability and activating the HIF-1α signaling pathway. However, whether other metabolites regulate HIF-1α stability remains unclear. Here, we reported that the enzyme in phenylalanine/tyrosine catabolism glutathione S-transferase zeta 1 (GSTZ1) deficiency led to accumulation of succinylacetone, which was structurally similar to α-ketoglutarate. Succinylacetone competed with α-ketoglutarate for PHD2 binding and inhibited PHD2 activity, preventing hydroxylation of HIF-1α, 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-1α/VEGFA axis in HCC. Moreover, we explored the therapeutic potential of HIF-1α inhibitor combined with anti-PD-L1 therapy to effectively prevent HCC angiogenesis and tumorigenesis in Gstz1-knockout mice, suggesting a potentially actionable strategy for HCC treatment.