SERINC3 promotes oral squamous cell carcinoma progression and mitochondrial metabolic reprogramming involving c-MET/JNK/PGC-1α axis.

Abstract

Serine incorporator 3 (SERINC3) is a multi-transmembrane protein involved in membrane lipid biosynthesis but its role in oral squamous cell carcinoma (OSCC) is undefined. Combining clinical specimens with public transcriptomic datasets, we found that SERINC3 was upregulated in OSCC tissues and that high expression was associated with poorer overall survival. Functionally, SERINC3 depletion impaired OSCC cell proliferation, migration, and invasion, whereas SERINC3 overexpression enhanced these phenotypes. In vivo, Serinc3 deletion suppressed 4NQO-induced oral tumorigenesis, and SERINC3 knockdown reduced tumor growth in both subcutaneous and patient-derived xenograft models. Mechanistically, SERINC3 sustained c-MET expression, and knockdown of either SERINC3 or MET increased JNK phosphorylation and PGC-1α levels; JNK inhibition with JNK-IN-8 partially reversed the phenotypic effects of SERINC3 depletion, while pharmacological PGC-1α activation with ZLN005 suppressed migration and invasion in vitro and xenograft growth in vivo. Single-cell RNA sequencing and metabolic assays further linked SERINC3 to mitochondrial metabolic reprogramming. Together, these findings identify SERINC3 as a candidate driver of OSCC progression acting through c-MET/JNK/PGC-1α-associated signaling and mitochondrial metabolic regulation, and suggest it as a potential therapeutic target. The precise causal relationships within this signaling axis warrant further investigation.