Sanguinarine Induces Pyroptosis via the Hippo Signaling Pathway and Remodels the Tumor Immune Microenvironment in Lung Adenocarcinoma.

Sanguinarine (SAN), a natural alkaloid derived from Papaveraceae plants, is an active component in traditional Chinese medicines. SAN exerts inhibitory effects on tumor cells, but research on its effects on lung adenocarcinoma (LUAD) and the underlying mechanisms remains limited. The Hippo signaling pathway is commonly downregulated in LUAD, making it a key target for therapeutic intervention. Our study reveals that SAN significantly inhibits LUAD. Mechanistically, SAN bound to Large Tumor Suppressor 1 (LATS1) and promoted its phosphorylation, thereby activating the Hippo pathway and pyroptosis in LUAD. Notably, YAP overexpression inhibited pyroptosis and weakened the antitumor effect of SAN, further confirming that SAN exerts its antitumor effects by regulating the Hippo-YAP axis. Findings from both in vivo experiments and single-cell RNA sequencing consistently show that SAN remodels the tumor immune microenvironment and inhibits tumor growth. Specifically, we observed significant changes in the tumor microenvironment, including increased CD8+ T cell infiltration and a notably reduced number of myofibroblastic cancer-associated fibroblasts. Collectively, our findings establish SAN as a candidate therapeutic agent that exerts antitumor effects through dual modulation of the Hippo-mediated pyroptosis pathway and tumor immunity, providing a mechanistic basis for its potential clinical application in LUAD.