Novel m5C-dependent post-transcriptional regulation of KIF11 drives lymphatic metastasis in gastric cancer.

Lymphatic metastasis is a critical determinant of poor prognosis in gastric cancer (GC), yet the underlying regulatory mechanisms remain incompletely understood. While kinesin family member 11 (KIF11) is known to promote lymphangiogenesis, its upstream post-transcriptional regulation in GC has not been elucidated. In this study, we demonstrate for the first time that KIF11 is a direct target of 5-methylcytosine (m5C) RNA modification, which is mediated by the methyltransferase NSUN2 and recognized by the m5C reader YBX1. Mechanistically, NSUN2 deposits m5C marks at specific sites on KIF11 mRNA, particularly at C94413695 and C94413832, which are subsequently recognized by YBX1 to enhance mRNA stability and elevate KIF11 expression. Functionally, upregulated KIF11 promotes lymphangiogenesis by facilitating the Golgi localization and secretion of pro-lymphangiogenic proteins, thereby accelerating lymph node metastasis in GC. These findings uncover a previously unrecognized NSUN2/YBX1–KIF11 regulatory axis and establish m5C-dependent post-transcriptional regulation as a key mechanism linking KIF11 upregulation to lymphangiogenesis and metastatic progression in GC. This study provides novel mechanistic insights and identified potential therapeutic targets for the treatment of metastatic GC.