Carbonyl reductase 4 suppresses colorectal cancer progression through the DNMT3B/CBR4/FASN/mTOR axis

Lipid metabolism is implicated in the initiation and progression of human colorectal cancer (CRC). Carbonyl reductase 4 (CBR4), a member of the carbonyl reductase family, plays a role in the biosynthesis of fatty acids. However, its involvement in CRC remains poorly understood. In this study, we aim to explore the function of CBR4 in CRC. Our findings indicated that the expression of CBR4 was significantly reduced in CRC tissues. Functional analyses revealed that CBR4 functions to inhibit cell proliferation, colony formation, migration, invasion, and tumor growth in vivo. Mechanistically, CBR4 interacts with fatty acid synthase (FASN), activating the ubiquitin-proteasome pathway, which leads to a reduction in FASN expression, thereby inhibiting the mTOR pathway and curtailing CRC development. Orlistat, a known FASN inhibitor, demonstrated anti-cancer properties both in vitro and in vivo. Additionally, DNMT3B, a DNA methyltransferase, contributed to the down-regulation of CBR4 by inducing methylation in the promoter region. In summary, our findings suggest that the DNMT3B/CBR4/FASN/mTOR signaling pathway is crucial in the advancement of CRC, and elucidate the potential mechanism by which enzymatic carbonyl reduction and lipid metabolism may be connected to CRC progression, offering a novel therapeutic strategy for its clinical management.