Aging-related signature stratifies LUAD prognosis and uncovers senescence-induced chemoresistance via NF-κB/RELA activation.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer and a leading cause of cancer-related mortality worldwide. Aging has emerged as a significant risk factor for LUAD, with evidence suggesting that age-associated biological changes may influence prognosis. However, the underlying molecular mechanisms linking aging to tumor progression and therapy resistance are not fully understood. METHODS: We integrated transcriptomic data from LUAD cohorts to identify aging-related genes that are differentially expressed and associated with prognosis. Then Cox regression was utilized to establish an aging-related signature. Patients were stratified based on the signature, and we examined survival differences and transcription factor expression between groups. In vitro, cellular senescence was induced in A549 cells by bleomycin treatment, and subsequent changes in gene expression, transcription factor activity, and chemoresistance were assessed. Mechanistic studies included RNA interference and inhibitor treatment to investigate the dependence of chemoresistance on specific signaling pathways. RESULTS: A six-gene (H2AX, IGFBP1, CCL20, TFAP2A, TNFRSF11A, TNFRSF13C) aging-related signature was identified, stratifying patients into low- and high-risk groups with distinct overall survival outcomes. High-risk patients exhibited significantly poorer survival. Transcriptomic and protein analyses revealed that the transcription factor RELA was specifically upregulated in high-risk and senescent cells. Functional studies confirmed that induction of cellular senescence increased RELA expression, NF-κB signaling activation and conferred resistance to paclitaxel. Notably, genetic knockdown or inhibition of NF-κB signaling restored chemosensitivity in senescent tumor cells without reversing the senescent phenotype itself. CONCLUSIONS: This study established a clinically relevant aging-related signature for risk stratification in LUAD and provides mechanistic insights into how aging-driven cellular senescence promotes chemoresistance through RELA/NF-κB pathway activation. Targeting NF-κB signaling may represent a promising therapeutic approach to overcome senescence-associated chemoresistance and improve outcomes for LUAD patients.