Hepatocellular carcinoma (HCC) remains a highly prevalent malignancy worldwide with limited therapeutic options and frequent resistance to treatment, necessitating the development of targeted pharmacological interventions. Although artesunate, a derivative of the widely used antimalarial drug artemisinin, has emerged as a promising anticancer candidate, the molecular basis underlying its antitumor activity in HCC has remained unclear.

Building on their previous study that identified glucosylceramidase (GBA) as a direct target of artesunate, this study published in Genes & Diseases by researchers from China Academy of Chinese Medical Sciences and Fujian University of Traditional Chinese Medicine elucidates the structural basis of this interaction and the downstream mechanisms responsible for its anticancer effects.

Using a combination of computational modeling, biochemical analyses, cellular assays, and in vivo experiments, the researchers demonstrated that artesunate markedly suppressed HCC cell proliferation while promoting apoptosis, with HepG2 cells exhibiting greater sensitivity than MHCC-97H cells. The antitumor effects were associated with disruption of sphingolipid homeostasis, accumulation of glucosylceramide-related metabolites, mitochondrial dysfunction, and activation of caspase-dependent apoptotic signaling pathways.

Mechanistically, network and experimental analyses identified a GBA–ceramide–CTSD–α-syn–BID–BAX signaling axis that mediates artesunate-induced apoptosis in HCC. Artesunate inhibits GBA, disrupting ceramide metabolism, impairing CTSD maturation, and promoting α-syn accumulation, which activates mitochondrial apoptosis through BID cleavage, BAX upregulation, and caspase activation. Rescue experiments with ceramide supplementation or α-syn inhibition confirmed the central role of this pathway in artesunate's anticancer activity.
Through integrated computational and experimental analyses, the authors identified Y313, E340, and N396 as critical binding residues within the GBA active site. Site-directed mutagenesis, particularly the E340R and N396R mutations, significantly impaired artesunate binding and reduced GBA enzymatic activity, thereby abolishing artesunate's ability to regulate downstream apoptotic signaling and establishing a direct mechanistic link between target engagement and therapeutic activity.

Collectively, this study provides the first detailed structural and mechanistic characterization of how artesunate directly targets GBA in HCC, identifying the GBA–ceramide–CTSD–α-syn–BID–BAX signaling axis as a key mediator of mitochondrial apoptosis. These findings establish GBA as a promising therapeutic target and advance understanding of artesunate's anticancer activity, supporting the rational development of GBA-targeted therapeutic strategies for HCC. While the proposed mechanism was validated in HCC cell lines and supported by in vivo studies, further validation in patient-derived organoids and xenograft models, together with comprehensive long-term safety assessments, will be essential to confirm its clinical relevance and support translation toward HCC therapy.

Reference
Title of the original paper: Artesunate directly targets glucosylceramidase to suppress hepatocellular carcinoma proliferation and trigger apoptosis
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2026.102045

Funding Information:
National Natural Science Foundation of China (No. 82104467, 82574854)
National Science and Technology Major Project for the Prevention and Control of Emerging and Major Infectious Diseases (No. 2025ZD01906000, 2025ZD01906004)
Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences (No. CI2023E001TS02, CI2023E001TS06, CI2023E002-Y-51)
Fundamental Research Funds for the Central Public Welfare Research Institutes (China) (No. ZZ15-YQ-029, ZXKT22042, ZXKT25035)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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