N‐glycosylation Modification of CTSD Affects Liver Metastases in Colorectal Cancer

Abstract Liver metastasis is the primary factor contributing to unfavorable prognosis in colorectal cancer (CRC). Although N ‐glycosylation is implicated in metastasis, there is a notable paucity of comprehensive studies addressing the N ‐glycosylation proteomics associated with liver metastasis in CRC. In this study, N‐ glycosylated proteins and N‐ glycosylation sites of differential expression between primary lesions and paired liver metastatic lesions are identified. Cathepsin D (CTSD) is further screened as a potentially pivotal N‐ glycosylated protein in CRC liver metastasis. Glycosyltransferases complex DDOST and STT3B can regulate N‐ glycosylation modification at residue 263 of CTSD (a protease), thereby affecting CTSD protease to lyse ACADM. ACADM can regulate ferroptosis‐related proteins (ACSL4, SLC7A11, and GPX4) to further influence the invasion and metastasis of CRC cells. This newly discovered mechanism provides potential therapeutic targets for CRC treatment and insights for controlling CRC progression and metastasis.