2. Academic Validation
  3. Neoprzewaquinone A suppresses hepatocellular carcinoma through promoting the ubiquitin-related degradation of EGFR and inhibiting PI3K-AKT pathway

Neoprzewaquinone A suppresses hepatocellular carcinoma through promoting the ubiquitin-related degradation of EGFR and inhibiting PI3K-AKT pathway

  • Eur J Pharmacol. 2025 Oct 21:1007:178274. doi: 10.1016/j.ejphar.2025.178274.
Chunyang Zhang 1,  Shunfei Liu 2,  Dan Han 1,  Lulu Zeng 2,  Panhui Guo 2,  Zhiwei Gao 1,  Xiaoyuan Luo 1,  Bo Guan 1,  Jiong Gu 3,  Xiangpeng Hu 4,  Jun Liu 5
Affiliations

Affiliations

  • 1 School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
  • 2 Department of Gastroenterology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 3 Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China. Electronic address: xiaxun2005@163.com.
  • 4 Department of Gastroenterology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China. Electronic address: huxiangpeng@ahmu.edu.cn.
  • 5 School of Basic Medical Sciences, Anhui Medical University, Hefei, China. Electronic address: liujun@ahmu.edu.cn.
PMID: 41130376 DOI: 10.1016/j.ejphar.2025.178274
Abstract

Background: Traditional Chinese medicine (TCM), with its multitargeted effects against tumors and holistic regulatory properties, is a promising candidate for hepatocellular carcinoma (HCC) therapy. Neoprzewaquinone A (NEO), a phenanthrenequinone derivative of Salvia miltiorrhiza Bunge with anti-tumor effect, inhibits the migration and proliferation of breast Cancer and human megakaryocytic leukemia cells. However, its function and the mechanism of action in HCC remain unclear.

Methods: To evaluate the anti-HCC effectiveness of NEO, we employed patient-derived organoids, HepG2 cell-derived xenograft model, and hepatoma cell lines. Techniques such as molecular docking, drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), Apoptosis anlysis, in vivo ubiquitination, and Western blot analysis were used to investigate the underlying molecular mechanisms.

Results: In the current study, the anti-HCC effectiveness of NEO was validated using human HCC organoids and HepG2 cell-derived xenograft model. Meanwhile, NEO treatment reduced the viability, proliferation, migration, invasion of hepatoma cells, and increased the Apoptosis ratio of hepatoma cells. Next, we found that NEO directly engaged with epidermal growth factor receptor (EGFR) with molecular docking, DARTS, and CETSA. NEO decreased the level of EGFR through promoting ubiquitin-related degradation. NEO treatment suppressed the levels of phosphorylated Akt (p-AKT) and phosphorylated Bad (p-Bad), and NEO treatment increased Cleaved Caspase-3 protein expression, as shown by KEGG pathway analysis, which also indicated that NEO modulates the PI3K-AKT signaling pathway.

Conclusions: NEO induces Apoptosis and suppresses HCC progression by promoting ubiquitin-mediated degradation of EGFR and inhibiting the PI3K-AKT signaling pathway. Our data show that NEO may represent a promising therapeutic agent for HCC.

Keywords

EGFR; Hepatocellular carcinoma; Neoprzewaquinone A; PI3K-AKT pathway; Ubiquitin-related degradation.

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