Comparative Analysis of the Effects of PSPH and PHGDH Inhibitors on Tumor Cell Proliferation

Abstract

Serine metabolism plays a critical 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 are solely dependent on serine metabolism remains under debate. In this study, we systematically compared the effects of PHGDH versus PSPH inhibitors on intracellular serine levels and tumor cell proliferation. Although multiple PSPH inhibitors significantly reduced intracellular serine concentrations, they failed to effectively inhibit cell proliferation. In contrast, PHGDH inhibitors exhibited robust antiproliferative activity under both serine-deprived and serine-replenished conditions. Further supplementation with -ketoglutarate, a downstream metabolite of PHGDH, partially reversed this inhibitory effect. These findings suggest that the antitumor activity of PHGDH inhibitors is not solely attributable to serine metabolism inhibition, but rather results from the coordinated disruption of multiple metabolic pathways, offering a novel perspective for metabolism-targeted cancer therapy.