Abstract

Metabolic reprogramming is a hallmark of lung adenocarcinoma (LUAD) progression and therapeutic resistance. Gasdermin C (GSDMC) is frequently upregulated in patients with LUAD and correlates with poor prognosis. Under nutrient stress or ionizing radiation, phosphorylated STAT3 at Ser727 transcriptionally induces GSDMC, which translocates into the nucleus via the IPO7-KPNB1-NUP93 complex. In the nucleus, GSDMC functions as a scaffold molecule, recruiting NAT10 to mediate histone H3 acetylation and recruiting BAZ1B/SMARCA5 to modulate chromatin remodeling and chromatin accessibility. These changes facilitate CAMKK2-AMPK pathway activation. The GSDMC-CAMKK2-AMPK axis promotes metabolic reprogramming toward glycolysis and fatty acid oxidation, supporting LUAD cell proliferation and survival. Importantly, GSDMC contributes to LUAD radioresistance through the STAT3-GSDMC-CAMKK2-AMPK axis, and targeting any component of this pathway enhances radiotherapy sensitivity in preclinical models. Our findings identify a regulatory role for GSDMC in LUAD progression via metabolic reprogramming and support its potential as a preclinical candidate target to improve radiotherapy response.