Lactylation shields S100A11 from degradation to promote gastric cancer metastasis

S100A11 was identified as significantly hyperlactylated in GC tissues, with K27 and K55 as the primary modification sites. Lactylation at these residues disrupted the interaction between S100A11 and its E3 ubiquitin ligase FBXW11, thereby inhibiting polyubiquitination and proteasomal degradation. The lactylation-refractory K27R/K55R mutant exhibited constitutive protein stabilization, which hyperactivated PI3K-AKT and ERK1/2 signaling cascades and upregulated Cyclin D1 and c-Myc. Functionally, this stabilization significantly enhanced GC cell proliferation, colony formation, migration, and invasion in vitro, and markedly promoted lung metastasis in vivo.