ADAMTSL2 facilitates ACLY-mediated lipid metabolism in colorectal cancer by activating Notch signaling pathway

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, characterized by complex metabolic alterations and aberrant signaling pathways. Although ADAMTSL2 has been associated with tumor progression, its functional role in CRC remains unclear. In this study, we identified elevated ADAMTSL2 expression in CRC tissues from the TCGA-COADREAD cohort, where it correlated with poor patient survival. Functional experiments using HCT116 and SW620 cell lines, along with patient-derived organoids, demonstrated that ADAMTSL2 knockdown suppressed proliferation and migration. These findings were further supported by reduced tumor growth in ADAMTSL2-silenced xenograft models. Mechanistically, we uncovered a novel ADAMTSL2-Notch-ACLY axis, through which ADAMTSL2 activates Notch signaling to transcriptionally upregulate ACLY, driving lipid metabolic reprogramming. Our results establish ADAMTSL2 as a key prognostic biomarker and a potential therapeutic target in CRC, highlighting the clinical relevance of its regulation of Notch-ACLY-mediated metabolic plasticity.