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

Abstract

BackgroundLung 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.MethodWe 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.ResultsThe 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.ConclusionOur 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.

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BibTeX

@article{cui2026morusin,
  title = {{Morusin induces GSDME-dependent pyroptosis in non-small cell lung cancer via the angiotensin II receptor type 2}},
  author = {Xiaoyue Cui and Qiqi Zhang and Junjie Hu and Xun Li and Chengjie Shu and Yixuan Xi and Shiqi Zheng and Shiyao Ma and Fan Li and Xinpeng Bai and Ganglu Liu and Hong Zhang and Wanyan Deng and Mengjun Bie and Huansha Yu and Dandan Yang},
  journal = {Frontiers in Pharmacology},
  year = {2026},
  month = nov,
  doi = {10.3389/fphar.2026.1970372},
  url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1970372},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Morusin induces GSDME-dependent pyroptosis in non-small cell lung cancer via the angiotensin II receptor type 2
AU  - Xiaoyue Cui
AU  - Qiqi Zhang
AU  - Junjie Hu
AU  - Xun Li
AU  - Chengjie Shu
AU  - Yixuan Xi
AU  - Shiqi Zheng
AU  - Shiyao Ma
AU  - Fan Li
AU  - Xinpeng Bai
AU  - Ganglu Liu
AU  - Hong Zhang
AU  - Wanyan Deng
AU  - Mengjun Bie
AU  - Huansha Yu
AU  - Dandan Yang
PY  - 2026
DA  - 2026/11/06
JO  - Frontiers in Pharmacology
DO  - 10.3389/fphar.2026.1970372
UR  - https://www.frontiersin.org/articles/10.3389/fphar.2026.1970372
AB  - BackgroundLung 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.MethodWe 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.ResultsThe 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.ConclusionOur 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.
SN  - 1663-9812
ER  -

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