4'-Hydroxywogonin Attenuates Hepatocellular Carcinoma Progression by Suppressing Gas6/Axl-PI3K/AKT Signaling.

Authors

Chi-Yuan Chen, Chin-Chuan Chen, Chau-Ting Yeh, Chieh-Wen Chan, Yu-De Chu, Yann-Lii Leu, Roshan B Satange, Li-Fang Chou, Wen-Yu Chuang, Chuen Hsueh, Tzong-Ming Shieh, Tong-Hong Wang

Published in

Phytotherapy research : PTR. Oct 28, 2026. Epub Oct 28, 2026.

Abstract

4'-Hydroxywogonin, a bioactive flavonoid derived from Scutellaria baicalensis, has reported anti-inflammatory and anticancer activities; however, its therapeutic potential and molecular mechanism in hepatocellular carcinoma (HCC) remain unclear. This study investigated the anti-tumor effects of 4'-hydroxywogonin and its regulatory role in Gas6/Axl-associated signaling. Human HCC cells were used to evaluate proliferation, migration, invasion, cell cycle distribution, apoptosis, senescence, and epithelial-mesenchymal transition. Whole-transcriptome sequencing, western blotting, quantitative polymerase chain reaction, molecular docking, and thermal shift analysis were performed to explore the underlying mechanism, and antitumor efficacy and safety were further examined in a mouse xenograft model. 4'-Hydroxywogonin significantly inhibited HCC cell proliferation, migration, and invasion, while inducing G1-phase arrest, apoptosis, and senescence. Transcriptomic and molecular analyses identified Axl as a key affected target. 4'-Hydroxywogonin reduced Gas6 and Axl expression, suppressed PI3K/AKT activation, and downregulated cell cycle and epithelial-mesenchymal transition (EMT)-related proteins. Molecular docking predicted a potential interaction between 4'-hydroxywogonin and Axl, which was supported by thermal shift analysis. Axl overexpression partially rescued the inhibitory effects of 4'-hydroxywogonin, suggesting involvement of Axl-dependent and additional pathways. In vivo, 4'-hydroxywogonin markedly reduced tumor growth with efficacy comparable to sorafenib and without evident hepatotoxicity. These findings indicate that 4'-hydroxywogonin suppresses HCC progression, at least in part, through inhibition of the Gas6/Axl-PI3K/AKT signaling axis, supporting its further development as a natural therapeutic candidate.

PMID:
42949541
Bibliographic data and abstract were imported from PubMed on 28 Oct 2026.

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