<p>Hepatocellular carcinoma (HCC) ranks among the most lethal cancers, and its dismal prognosis underscores the urgent need to elucidate the underlying carcinogenic mechanisms. Endoplasmic reticulum lipid rafts associated protein 2 (ERLIN2), an endoplasmic reticulum protein, has been implicated in various malignant tumors. However, its functional role in HCC remains poorly understood. Here, we found elevated ERLIN2 expression and N-glycosylation modification at asparagine 106 (N106) in HCC. We identify site-specific N-glycosylation as a crucial advantage of ERLIN2 that may result in aberrant cancer cell growth. Overexpression of either N-glycosylated ERLIN2 (wild-type, WT) or an asparagine-to-glutamine mutant (N106Q) in HCC cell lines indicated that N106 N-glycosylation of ERLIN2 acts as an important advantage in the tumorigenesis and triggers aberrant cell proliferation, migration, and invasion. Furthermore, we found that E3 ubiquitin ligase membrane-associated ring-CH-type finger protein 6 (MARCHF6) can mediate the ubiquitination degradation of ERLIN2, and this effect is more significant after the N-glycosylation at the N106 site is inhibited. In addition, excessive N-glycosylation at this site enhanced the interaction between ERLIN2 and cyclin B1 (CCNB1), leading to dysregulated CCNB1 expression and further accelerating the progression of HCC. Comprehensive studies confirm that N-glycosylation is a significant post-translational modification of ERLIN2 in HCC, and elucidating this mechanism may pave the way for the development of novel therapeutic strategies in the future.</p>