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We demonstrate that epigenetic silencing of otubain 2 (OTUB2), a previously recognized oncogene, drives SSCs initiation and drug resistance. Mechanistically, OTUB2 promotes deubiquitination and phosphorylation of signal transducer and activator of transcription 1 (STAT1), then activates transcriptional regulation of calmodulin-like protein 3 (CALML3). Activation of CALML3-mediated mitochondrial calcium signaling promotes oxidative phosphorylation (OXPHOS) and glycerophospholipid synthesis, among which phosphatidylserine (PS) is the most obviously affected. Orally administered soybean-derived PS dramatically inhibits low-OTUB2-expressed SCC initiation and increased sensitivity to chemotherapy in various mouse models. Our study indicates that the OTUB2/STAT1/CALML3/PS axis plays a critical tumor-suppressive role in SCCs, clarifies the low incidence of oral and esophageal SCCs in Western countries with a high-fat diet and demonstrates the potential of food supplementation with PS as a strategy for treatment and prevention of SCCs. Overall design: RNA-seq of OTUB2 overexpressed and control KYSE150 cells after administrating phosphatidylserineENAfalseSoybean derived phosphatidylserine synthetically targets OTUB2 epigenetic silencing in squamous cell carcinomaSoybean derived phosphatidylserine synthetically targets OTUB2 epigenetic silencing in squamous cell carcinoma2025-09-242022-10-07PRJNA721679GSE1720019606