Dihydroartemisinin Suppresses Hepatocellular Carcinoma Progression by Acting on KIF11 with PI3K/Akt Modulation

Background/Objectives: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with limited effective therapies. Dihydroartemisinin (DHA), a derivative of artemisinin, exhibits potent antitumor activity, but its molecular mechanisms in HCC are unclear. Here, we identified kinesin family member 11 (KIF11) as a critical effector of DHA. Methods: Bioinformatic analyses revealed that KIF11 is significantly upregulated in HCC and associated with poor prognosis, and gene expression profiling suggested its oncogenic role via the PI3K/Akt pathway. Functional studies demonstrated that DHA inhibits HCC cell proliferation, migration, invasion, and colony formation, while inducing apoptosis. Xenograft models of nude mice were established for validation. Results: DHA downregulated KIF11 and epithelial–mesenchymal transition markers, whereas KIF11 overexpression attenuated DHA’s inhibitory effects; the inhibition of PI3K restored DHA sensitivity in KIF11-overexpressing cells. In vivo, DHA markedly suppressed tumor growth and malignancy in xenograft models, consistent with modulation of KIF11 and EMT-related proteins. Conclusions: DHA exerts antitumor effects in HCC by acting via KIF11 and PI3K/Akt modulation, providing a potential therapeutic strategy.