# Kuwanon A Targeted YWHAB in Hepatocellular Carcinoma Cells to Inhibit the Raf/MEK/ERK Signaling Pathway

## TL;DR

Kuwanon A, a compound from mulberry, inhibits liver cancer cell growth and spread by targeting YWHAB and blocking a key signaling pathway.

## Contribution

Kuwanon A is shown to directly target YWHAB and synergize with sorafenib to inhibit HCC progression.

## Key findings

- Kuwanon A inhibits HCC cell proliferation and metastasis in vitro and in vivo.
- Kuwanon A disrupts YWHAB dimerization and inhibits the Raf/MEK/ERK signaling pathway.
- Combining Kuwanon A with sorafenib enhances anti-tumor effects in HCC cells.

## Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and the lung is one of the most frequent metastatic sites for HCC. In this study, we aimed to identify a mild active substance in Morus alba L. that can inhibit the pulmonary metastasis of HCC and reduce the drug resistance of clinical therapies. Further deepen the understanding of the anti-cancer functions of the mulberry active substances. In this study, we have screened and identified a flavonoid compound extracted from the root bark of the Morus alba L. named Kuwanon A (KA). Our research demonstrated that KA directly targeted the YWHAB (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta) and mediated its dimer dissociation. Thereby inhibiting the MAPK pathway and affecting downstream biological functions, including cell cycle arrest and migration/invasion inhibition. The experiment results proved that KA could inhibit the proliferation and metastasis of highly metastatic HCC cells both in vitro and in vivo. Additionally, when KA was combined with the clinical drug sorafenib, it exhibited a synergistic effect in inhibiting HCC cell proliferation, migration, and invasion. In conclusion, KA demonstrated a favorable anti-tumor effect in HCC cells.