Abstract

The incidence of obesity and colorectal cancer (CRC) is rising annually. Obesity, particularly visceral obesity, poses a serious health threat, yet the association of obesity with CRC progression, as well as the role of visceral obesity, remains debated. This study analyzed 394 CRC patients and revealed that both high body mass index (BMI) and visceral fat area (VFA) correlated with poor prognosis, with VFA being an independent risk factor. RNA sequencing and TCGA analysis showed that methyltransferase-like protein 27 (METTL27) was overexpressed in CRC tissues from patients with obesity (especially visceral obesity), and was associated with poor prognosis. Mechanistically, METTL27 activates the PPARD/CPT1A axis in an FABP5-dependent manner to promote CRC cell proliferation, migration, and invasion. Lipid metabolomics identified visceral obesity-specific fatty acids. In vitro, treatment with adipose tissue-conditioned medium (ACM) or visceral obesity-associated fatty acids induced lipid droplets accumulation and enhanced METTL27/FABP5/PPARD/CPT1A signaling, exacerbating CRC malignancy. This study is the first to elucidate METTL27's biological function, identifying it as a key upstream partner of FABP5, delineating its regulation of the FABP5/PPARD/CPT1A axis and its role in driving CRC progression in the context of visceral obesity, thereby providing new directions for therapeutic targets in CRC patients with visceral obesity.