<scp>PSAT1</scp> Promotes <scp>NSCLC</scp> Progression via the <i>De Novo</i> Serine Synthesis Pathway and Represents a Therapeutic Vulnerability

ABSTRACT Background Non‐small cell lung cancer (NSCLC) is a malignant tumor characterized by high morbidity and mortality, as well as metabolic reprogramming. Enhanced serine synthesis plays a crucial role in the aberrant metabolism of NSCLC. Among the three key enzymes involved in serine synthesis, phosphoserine aminotransferase 1 ( PSAT1 ) requires further investigation to elucidate its regulatory mechanisms in NSCLC. Methods In this study, we employed bioinformatics analysis, immunohistochemistry, CCK‐8 assay, colony formation assay, flow cytometry assay, isotope tracing technique, WB analysis, and nude mouse xenograft models to validate the expression and function of PSAT1 in NSCLC. Results Our results demonstrated that PSAT1 was significantly upregulated in NSCLC cells and contributed to promoting cell proliferation, inhibiting apoptosis, and attenuating the efficacy of gefitinib treatment. Moreover, knockdown of PSAT1 led to inhibition of the de novo serine synthesis pathway (SSP), elevation of reactive oxygen species (ROS) levels, and activation of the mitochondrial apoptotic pathway. Notably, combined knockdown of PSAT1 with exogenous serine intake inhibition synergistically suppressed NSCLC progression. Conclusion Collectively, our findings highlight that PSAT1 serves as a biomarker for metabolic reprogramming in NSCLC and exhibits a close association with disease development and treatment.