Chebulagic acid targets FBXO38 to enhance natural killer cell-mediated anti-tumor immunity in lung adenocarcinoma.

Lung adenocarcinoma (LUAD), the most prevalent and aggressive form of non-small cell lung cancer. Natural compounds have gained increasing attention as potential anti-cancer agents. The therapeutic potential of chebulagic acid (CA)-a hydrolysable tannin with documented anti-proliferative properties-has not been investigated in LUAD. In the present study, functional experiments revealed that CA treatment markedly suppressed proliferation and induced mitochondrial-dependent apoptosis of LUAD cells. In addition, CA augments natural killer (NK) cell migration by enhancing LUAD CCL5 production. Quantitative proteomics identified FBXO38 as the most significantly upregulated protein following CA treatment. FBXO38 silencing abrogated CA-induced CCL5 production and NK cell migration in LUAD cells. The in vivo experiments showed that CA significantly inhibited tumor growth and enhanced NK cell infiltration in mice, accompanied by decreased Ki67+ proliferating cells, increased cleaved caspase-3+ apoptotic cells, and upregulated FBXO38 expression. Collectively, our findings demonstrate that CA may be exert anti-LUAD effects through FBXO38/CCL5-mediated NK cell recruitment.