Dihydroartemisinin: A Promising Therapeutic Agent Against the Hepatitis-to-Hepatocellular Carcinoma Cascade

Liver cancer progression is a multifactorial, multistage, and complex malignancy. Dihydroartemisinin (DHA) is widely recognized for its antimalarial, antifibrotic, and anticancer activities. This review highlights that DHA in the hepatitis-to-hepatocellular carcinoma (HCC) cascade and explores its underlying mechanisms. DHA has remarkable effectiveness in suppressing inflammatory cytokines and promoting tissue recovery, primarily targeting the phosphoinositide 3-Kinase (PI3K)/protein kinase B (Akt) and interleukin signaling pathways. During hepatic fibrosis, DHA inhibits hepatic stellate cell activation through mechanisms including α-smooth muscle actin (α-SMA) and nuclear factor kappa B (NF-kB) pathways. It further modulates inflammatory responses, suppresses hematopoietic stem cell proliferation, induces ferroptosis, and regulates lipid droplet metabolism. Moreover, DHA inhibits the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway and yes-associated protein 1 (YAP1) signaling, thereby suppressing the proliferation, invasion, and metastatic potential of HCC cells, while simultaneously activating apoptotic and autophagic pathways. Additionally, it counteracts drug resistance and improves responsiveness to chemotherapy. Notably, lipid metabolism is identified as a promising therapeutic target in this cascade, and some nanoparticle drug delivery systems have been demonstrated to optimize DHA's therapeutic efficacy. DHA demonstrates broad therapeutic efficacy by targeting multiple molecular pathways, supporting its potential clinical application in hepatocellular carcinoma prevention and treatment.