Loss of the RAGE function in hypoxic conditions exacerbates the malignant progression of lung adenocarcinoma via damage-associated molecular pattern signaling.

Despite therapeutic advances, lung adenocarcinoma (LUAD) remains difficult to treat, and the mechanisms by which hypoxia promotes tumor progression are still incompletely understood. Because the receptor for advanced glycation end products (RAGE) has been implicated in hypoxia-related signaling, we investigated the interaction between damage-associated molecular patterns (DAMPs) and RAGE in LUAD under hypoxic conditions using the RAGE inhibitor FPS-ZM1 in vitro and in vivo. RAGE expression was significantly reduced in LUAD samples and was associated with poor survival. LUAD tissues also showed evidence of hypoxia, including elevated hypoxia-inducible factor-1α (HIF-1α). Under hypoxia, S100A8/A9 redistributed from the nucleus to the cytoplasm, whereas intracellular HMGB1 levels decreased. In vitro, FPS-ZM1 suppressed NF-κB phosphorylation and inhibited LLC cell viability and migration. In contrast, in vivo FPS-ZM1 treatment was associated with enhanced tumor progression, increased HIF-1α and S100A8/A9 expression, and reactivation of NF-κB signaling. These findings suggest that RAGE blockade may trigger context-dependent compensatory responses within the tumor microenvironment. We therefore present a working model in which a hypoxia-associated HIF-1α/S100A8/A9 axis may bypass RAGE inhibition and restore pro-tumor signaling; however, this mechanism requires direct experimental validation. Overall, our data highlight the importance of tumor-microenvironment context when interpreting RAGE-targeted interventions in LUAD.