AHSG confers apoptosis resistance in lung adenocarcinoma by modulating the GSK3β/β-catenin axis

Recent studies have demonstrated that alpha-2-Heremans-Schmid glycoprotein (AHSG) is significantly upregulated in lung adenocarcinoma (LUAD), where it correlates with poor prognosis and serves as an independent prognostic factor in LUAD patients. It promotes tumor progression by enhancing cell proliferation, migration, and invasion through modulation of TGFβ/PI3K-Akt signaling and induction of epithelial-mesenchymal transition (EMT). Although the proliferative effect of AHSG is well established, its role in regulating anti-apoptotic functions and the underlying molecular mechanisms remains unexplored. In the present study, we demonstrated that elevated cytoplasmic AHSG in LUAD serves as a critical regulator of programmed cell death by targeting the GSK3β/β-catenin axis. Mechanistically, cytoplasmic AHSG interacts with GSK3β and promotes its TRAF6-mediated ubiquitination and degradation, thereby relieving β-catenin repression and facilitating its nuclear translocation. Nuclear accumulation of β-catenin in LUAD cells considerably inhibits apoptosis, thereby promoting tumor survival. Interestingly, AHSG ablation markedly inhibited the GSK3β/β-catenin pathway, leading to induction of apoptosis in LUAD cells. These findings reveal a fundamental role of AHSG in driving LUAD cancer progression and suggest that targeting AHSG may be a potential therapeutic strategy for LUAD management.