糖酵解中间代谢产物，如果糖-1，6-二磷酸，可作为信号分子，控制超越能量代谢的代谢状态。然而，糖酵解代谢产物是否在调控细胞命运方面也发挥作用尚未被探索。在这里，我们发现低水平的糖酵解代谢产物3-磷酸甘油酸（3-PGA）可以将磷酸甘油酸脱氢酶（PHGDH）从卡伐普勒诺丝合成转变为促凋亡的p53激活。PHGDH是一个与p53结合的蛋白质，并且在未被3-PGA占据时，与AXIN蛋白质和激酶HIPK2结合，这两者也均是p53结合蛋白质。这导致形成了一个多价p53结合复合物，使HIPK2能够特异性地磷酸化p53-Ser46，从而促进凋亡。此外，我们显示，与3-PGA不断结合的PHGDH突变体（R135W和V261M）即使在低葡萄糖条件下也能抑制p53激活，而无法结合3-PGA的突变体（T57A和T78A）导致肝细胞癌（HCC）细胞中持续的p53激活和凋亡，即使存在高葡萄糖。在体内，PHGDH-T57A诱导凋亡并抑制二乙基亚硝胺诱导的小鼠HCC的生长，而PHGDH-R135W则阻止凋亡并促进HCC的生长，而Trp53的敲除会使上述效应消失。重要的是，降低全身葡萄糖水平的限制热量摄入可以延缓依赖于PHGDH的HCC的生长。综上所述，这些结果揭示了葡萄糖可获得性如何自主地调控p53活性的机制，为代谢底物可用性调控细胞命运提供了一个新的范例。©2023年。作者。

Glycolytic intermediary metabolites such as fructose-1,6-bisphosphate can serve as signals, controlling metabolic states beyond energy metabolism. However, whether glycolytic metabolites also play a role in controlling cell fate remains unexplored. Here, we find that low levels of glycolytic metabolite 3-phosphoglycerate (3-PGA) can switch phosphoglycerate dehydrogenase (PHGDH) from cataplerosis serine synthesis to pro-apoptotic activation of p53. PHGDH is a p53-binding protein, and when unoccupied by 3-PGA interacts with the scaffold protein AXIN in complex with the kinase HIPK2, both of which are also p53-binding proteins. This leads to the formation of a multivalent p53-binding complex that allows HIPK2 to specifically phosphorylate p53-Ser46 and thereby promote apoptosis. Furthermore, we show that PHGDH mutants (R135W and V261M) that are constitutively bound to 3-PGA abolish p53 activation even under low glucose conditions, while the mutants (T57A and T78A) unable to bind 3-PGA cause constitutive p53 activation and apoptosis in hepatocellular carcinoma (HCC) cells, even in the presence of high glucose. In vivo, PHGDH-T57A induces apoptosis and inhibits the growth of diethylnitrosamine-induced mouse HCC, whereas PHGDH-R135W prevents apoptosis and promotes HCC growth, and knockout of Trp53 abolishes these effects above. Importantly, caloric restriction that lowers whole-body glucose levels can impede HCC growth dependent on PHGDH. Together, these results unveil a mechanism by which glucose availability autonomously controls p53 activity, providing a new paradigm of cell fate control by metabolic substrate availability.© 2023. The Author(s).