OSBPL3 regulates colorectal cancer progression by modulating gut microbiota and tumor immune microenvironment

Abstract This study aimed to explore the biological function of Oxysterol Binding Protein-Like 3 (OSBPL3) in colorectal cancer (CRC) and its potential to regulate gut microbiota homeostasis, providing insights for individualized CRC prevention and treatment. Using public databases, we analyzed OSBPL3’s role in CRC, validated its prognostic value via clinical data and IHC, and identified its impact on CRC progression through functional assays and an orthotopic model. After in vivo OSBPL3 knockdown, we collected mouse feces, blood, and colorectal tissue, and used multi-omics analyses (16S rRNA sequencing, metabolomics, transcriptomics) to link OSBPL3 to gut microbiota, metabolic pathways, and differentially expressed genes, locating key microbes which were further verified in vitro and vivo to uncover their immune-related anti-CRC mechanisms. Results showed elevated OSBPL3 in CRC tissues correlated with poor prognosis; OSBPL3 knockdown reduced CRC cell proliferation, migration, invasion, and increased apoptosis, while altering gut microbiota composition (e.g., increased Eubacterium ruminantium and Roseomonas ) and metabolic pathways. Administering these bacteria to mice enhanced intratumoral CD8+ T cell proportion, linking CRC inhibition to improved immune surveillance. Conclusion : OSBPL3 promotes CRC by disrupting gut microbiota and immune homeostasis; targeting E. ruminantium and Roseomonas may offer a novel CRC therapy.