PTDSS1 Drives Glycolysis and Malignant Progression of Lung Cancer Through Maintaining Nuclear–Mitochondrial Homeostatic Crosstalk

Background: Phosphatidylserine synthase 1 (PTDSS1) is a crucial enzyme involved in phospholipid synthesis. However, its role in the metabolic regulation of lung cancer remains unclear. This study hypothesized that PTDSS1 promotes lung cancer progression by regulating metabolic reprogramming through nuclear–mitochondrial crosstalk. Methods: PTDSS1’s expression levels in lung cancer tissues and their correlation with patient prognosis were evaluated through bioinformatics analysis and immunohistochemistry. In vitro functional experiments, including cell proliferation, migration, invasion, and colony formation, were performed using PTDSS1-overexpressing lung cancer cell lines. Cellular glycolysis and mitochondrial oxidative phosphorylation levels were determined. PTDSS1’s subcellular localization was investigated through cellular fractionation and immunofluorescence. Its regulatory interaction with pyruvate kinase M2 (PKM2) was examined. Expression levels of metabolism-related genes and mitochondrial dynamics markers were analyzed by qRT-PCR and Western blot. Results: PTDSS1 was significantly overexpressed in lung cancer tissues. High PTDSS1 expression correlated with poor patient prognosis. PTDSS1 enhanced lung cancer cell proliferation, migration, and invasion capabilities. Metabolically, PTDSS1 promoted aerobic glycolysis. Mitochondrial oxidative phosphorylation was suppressed. Nuclear-localized PTDSS1 showed enhanced effectiveness in driving glycolysis and malignant progression. Mechanistically, PTDSS1 may accelerate glycolysis through PKM2 regulation. It may drive lung cancer progression through PKM2-mediated nuclear–mitochondrial homeostatic crosstalk. Conclusion: PTDSS1 functions as a multifunctional oncogene. It drives lung cancer progression through PKM2-mediated nuclear–mitochondrial homeostatic crosstalk. PTDSS1 represents a potential prognostic biomarker and therapeutic target.