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

ABSTRACT 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.