FUCA2 Sustains AKT Signaling and Suppresses Senescence by Antagonizing FUT3-Mediated ErbB3 Fucosylation in Lung Adenocarcinoma.

While targeted therapies have improved outcomes in lung adenocarcinoma (LUAD), many patients still lack targetable mutations. Here, we identified alpha-L-fucosidase 2 (FUCA2) as a crucial driver of LUAD by preventing cellular senescence. Mechanistically, through the restriction of fucosyltransferase 3 (FUT3)-mediated α-1,3-fucosylation of ErbB3 at Asn437, FUCA2 safeguarded ErbB3-ErbB2 heterodimerization to promote ErbB3 activation and sustain persistent AKT signaling. Active AKT prevented p53 protein stabilization in TP53-wild-type LUAD cells and inhibited p27 protein accumulation in TP53-mutant LUAD cells, thereby counteracting senescence and supporting malignant growth. Notably, low-dose Capivasertib, an AKT inhibitor targeting tumors with PIK3CA/AKT1/PTEN mutation(s), induced senescence selectively in FUCA2-high LUAD irrespective of PIK3CA/AKT1/PTEN/TP53 mutational status, and its combination with the nutraceutical senolytic procyanidin C1 achieved potent and low-toxicity suppression of LUAD across multiple preclinical models. Together, our results uncover the FUCA2-ErbB3 fucosylation-AKT pathway as a central regulator of senescence and propose a FUCA2-guided drug repurposing strategy for LUAD.