MOGAT2 suppresses colorectal cancer progression through ACSM1-mediated lipid metabolic reprogramming

Colorectal carcinogenesis and progression are closely associated with metabolic dysregulation. The role of MOGAT2 in colorectal cancer (CRC) advancement and its underlying metabolic mechanisms remain unclear. This study aimed to explore how MOGAT2 influences tumorigenesis by modulating lipid metabolism.

MOGAT2 expression was assessed in four CRC cell lines using qRT-PCR and Western blot. Functional consequences of MOGAT2 modulation were examined following siRNA-mediated knockdown or lentivirus-mediated overexpression in HCT116/SW620 cells. Assays measured cell proliferation, colony formation, apoptosis, invasion, and epithelial-mesenchymal transition (EMT). Key lipid metabolites and metabolic enzymes were analyzed. A CRC xenograft mouse model was used for in vivo validation. RNA sequencing and rescue experiments identified ACSM1 as a key downstream mediator.

MOGAT2 knockdown enhanced cell proliferation, colony formation, and invasion, as well as inhibited apoptosis. While its overexpression significantly suppressed malignant phenotypes, induced apoptosis, and inhibited EMT. Mechanistically, MOGAT2 modulated lipid metabolism by reducing FFA accumulation and regulating cholesterol transport, accompanied by downregulation of lipid synthesis enzymes (GPAT2, GPAT3, and GAAT). In vivo, MOGAT2 overexpression inhibited tumor growth, improved histopathology, and restored lipid balance. Crucially, ACSM1 was identified as a critical downstream effector. Silencing ACSM1 abolished the tumor-suppressive effects of MOGAT2 overexpression, reinstating aggressive growth, suppression of apoptosis, EMT, and metabolic dysregulation.

MOGAT2 functions as a tumor suppressor in CRC by inhibiting proliferation, promoting apoptosis, and suppressing invasion/EMT via ACSM1-mediated metabolic reprogramming, highlighting its potential as a therapeutic target.