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

Current therapies are often limited by resistance, toxicity, or poor efficacy, highlighting the urgent need for novel strategies. Here, we performed a high-throughput screen for compounds and identified that morusin could activate gasdermin E (GSDME), which is expressed in non-small-cell lung cancer.

Using a genome-wide CRISPR/Cas9 screen, we identified AGTR2 as a critical regulator of morusin-induced pyroptosis, which acts via activation of the caspase-3–GSDME signaling cascade. In mouse tumor models, pyroptosis induced by morusin suppresses tumor growth without cause weight loss. Thus, our study uncovers a novel mechanism through which morusin exerts its anti-tumor effect, thereby establishing AGTR2 as a potential therapeutic target and providing a rationale for pyroptosis-based non-small-cell lung cancer therapy.