Morusin induces GSDME-dependent pyroptosis in non-small cell lung cancer via the angiotensin II receptor type 2

Background Lung cancer remains the leading cause of cancer-related mortality worldwide, its 5-year survival rate continues to be unsatisfactory. Current therapies are often limited by resistance, toxicity, or poor efficacy, highlighting the urgent need for novel strategies. Method We performed a high-throughput compound screen for inducing cell death in non-small cell lung cancer (NSCLC) cells. Combined with lactate dehydrogenase (LDH) release assays, cell death morphology observation, and propidium iodide (PI) staining, we confirmed the cell death mode as pyroptosis. Then, we conducted a genome-wide CRISPR/Cas9 screen to identify the critical regulator of compound-induced pyroptosis. Results The screening results showed that morusin is a trigger of gasdermin E (GSDME)-mediated pyroptosis in non-small cell lung cancer (NSCLC) cells. Importantly, morusin suppresses tumor growth in vivo . Through a genome-wide CRISPR/Cas9 screen, we further demonstrated that angiotensin II receptor type 2 (AGTR2) as a critical regulator of morusin-induced pyroptosis, acting via activation of the caspase-3–GSDME signaling cascade. Notably, morusin also upregulated AGTR2 expression in NSCLC cells. In an NSCLC mouse model, morusin treatment potently suppressed wild-type tumor growth, whereas its antitumor efficacy was substantially diminished in AGTR2-knockout tumors. Conclusion Our study reveals a novel mechanism underlying the antitumor effect of morusin, establishes AGTR2 as a potential therapeutic target, and provides a rationale for pyroptosis-based therapy for NSCLC.