Comparative analysis of the effects of PSPH and PHGDH inhibitors on tumor cell proliferation

Serine metabolism plays a pivotal role in supporting the rapid proliferation of tumor cells, with PHGDH recognized as a key rate-limiting enzyme and therapeutic target. However, whether its antitumor effects rely exclusively on serine metabolism remains controversial. In this study, we compared the effects of PHGDH and PSPH inhibitors on serine metabolism and cell proliferation in the breast cancer cell lines HCC-70 and BT-20. While two PSPH inhibitors markedly reduced cellular serine M + 3 levels, they failed to effectively inhibit cell proliferation. In contrast, PHGDH inhibitors exhibited robust antiproliferative activity under both serine-deprived and serine-supplemented conditions. Furthermore, supplementation with α-ketoglutarate, a downstream metabolite of PHGDH, partially reversed this inhibitory effect. These findings indicate that the antitumor activity of PHGDH inhibition cannot be solely attributed to blockade of serine biosynthesis, but rather arises from the coordinated disruption of multiple metabolic pathways. This provides new insights into the potential of metabolic targeting strategies for cancer therapy.