4′‐Hydroxywogonin Attenuates Hepatocellular Carcinoma Progression by Suppressing Gas6/Axl‐ PI3K / AKT Signaling

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.