Targeting phosphatidylserine for tumor cell suppression [RNA-seq]

Alterations in lipid metabolism are frequently observed in cancers, playing a pivotal role in tumor cell survival and proliferation. Phosphatidylserine (PS), the most negatively charged glycerophospholipid in eukaryotic membranes, is synthesized in mammals by key enzymes, such as phosphatidylserine synthase 1 (PTDSS1). Here, we identify a PS-dependent metabolic vulnerability in esophageal squamous cell carcinoma (ESCC) and glioblastoma (GBM). Pharmacological inhibition of PTDSS1 potently suppresses tumor growth with nanomolar efficacy. Mechanistically, PS depletion causes a metabolic depletion of PS and phosphatidylethanolamine (PE), triggering endoplasmic reticulum (ER) stress and activating autophagy. These findings reveal an unrecognized PS-dependent metabolic dependency for tumor cell viability, indicating that targeting PS synthesis may offer a promising therapeutic approach for tumor cell suppression.