# EM2, a Natural Product MST1/2 Kinase Activator, Suppresses Non‐Small Cell Lung Cancer via Hippo Pathway Activation

## TL;DR

EM2, a natural product, activates MST1/2 to suppress non-small cell lung cancer by inhibiting YAP and reducing tumor growth.

## Contribution

EM2 is identified as a high-selectivity MST1/2 activator with strong anti-NSCLC efficacy.

## Key findings

- EM2 suppresses NSCLC cell proliferation, migration, and invasion by activating MST1/2 and the Hippo pathway.
- EM2 reduces YAP nuclear translocation and downstream gene expression in NSCLC cells.
- In vivo and organoid models show EM2 effectively inhibits NSCLC tumor growth.

## Abstract

Lung cancer, 85% of which is non‐small cell lung cancer (NSCLC), is the cancer with the highest incidence and mortality rate worldwide. Despite recent advancements in therapeutic approaches, the efficacy of conventional radiotherapy and chemotherapy remains suboptimal, highlighting the urgent need for more effective treatment strategies. Dysregulation of kinases MST1 and MST2 (MST1/2) is implicated in the progression of NSCLC, positioning MST1/2 as a potential therapeutic target. However, no high‐selectivity and high‐efficacy MST1/2 activator is identified to date. In this study, by using computer‐aided virtual screening combined with cell experiments, EM2 is identified as a promising MST1/2‐binding candidate. Subsequent experimental validation demonstrates that EM2 significantly suppresses the proliferation, migration, and invasion of NSCLC cells by directly targeting MST1/2 and enhancing its kinase activity, thereby activating the Hippo signaling pathway and reducing nuclear translocation of the downstream effector YAP. Both in vivo xenograft models and organoid models demonstrates that EM2 effectively suppresses NSCLC tumor growth. In summary, this study not only reaffirms MST1/2 as a viable therapeutic target for NSCLC but also provides compelling experimental evidence supporting EM2 as a highly effective and promising anti‐cancer agent.

EM2 directly binds to and activates MST1/2, enhancing their kinase activity and sequentially promoting LATS phosphorylation, which increases YAP phosphorylation. Consequently, YAP nuclear translocation is suppressed, leading to reduced transcription of downstream targets CTGF and CYR61, ultimately exerting a robust inhibitory effect on NSCLC cell proliferation, migration, and tumor growth.