picture:
(A, B) Viability inhibitory curves of HepG2 and MHCC-97H cells induced by artesunate utilizing the CCK8 assay and the corresponding IC50 calculation. (C, D) Results of artesunate on the cell proliferation of HepG2 and MHCC-97H cells utilizing CCK8 assay. (E, G) Results of artesunate on the cell apoptosis of samples obtained from the HCC orthotopic mouse mannequin examined by TUNEL and Hoechst staining. Scale bars, 100 μm. CON: sham operation group; HepG2: 3 × 106 HepG2 cells had been injected into the appropriate lobe of the liver to induce HCC orthotopic mouse mannequin; ART-L, ART-M, ART-H: low- (5 mg/kg), middle- (10 mg/kg), high- (20 mg/kg) dose of artesunate remedy teams; ART-H + LTI-291: excessive dose of artesunate and GBA enzyme activator LTI-291 mixed remedy group. (F, H) Results of artesunate on the cell apoptosis of HepG2 cells examined by TUNEL and Hoechst staining. Scale bars, 100 μm. CON: HepG2 management group. ART-L, ART-M, ART-H: low-, middle-, and high-dose of artesunate remedy teams. 5-FU: optimistic drug 5-fluorouracil remedy group. ART-H + LTI-291: excessive dose of artesunate and GBA enzyme activator LTI-291 remedy group. The proportion of apoptotic cells derived from a minimum of 5 random fields of view (n = 3) was analyzed by two unbiased observers who had been blinded to the experimental teams. Information had been expressed as imply ± commonplace deviation. ∗P < 0.05, ∗∗P < 0.01, and ∗∗∗P < 0.001.
Credit score: Xia Mao, Xiangying Yan, Yawen Chen, Bingbing Cai, Wenjia Chen, Ya Lin, Na Lin, Yanqiong Zhang
Hepatocellular carcinoma (HCC) stays a extremely prevalent malignancy worldwide with restricted therapeutic choices and frequent resistance to remedy, necessitating the event of focused pharmacological interventions. Though artesunate, a spinoff of the broadly used antimalarial drug artemisinin, has emerged as a promising anticancer candidate, the molecular foundation underlying its antitumor exercise in HCC has remained unclear.
Constructing on their earlier examine that recognized glucosylceramidase (GBA) as a direct goal of artesunate, this examine revealed in Genes & Illnesses by researchers from China Academy of Chinese language Medical Sciences and Fujian College of Conventional Chinese language Drugs elucidates the structural foundation of this interplay and the downstream mechanisms chargeable for its anticancer results.
Utilizing a mixture of computational modeling, biochemical analyses, mobile assays, and in vivo experiments, the researchers demonstrated that artesunate markedly suppressed HCC cell proliferation whereas selling apoptosis, with HepG2 cells exhibiting larger sensitivity than MHCC-97H cells. The antitumor results had been related to disruption of sphingolipid homeostasis, accumulation of glucosylceramide-related metabolites, mitochondrial dysfunction, and activation of caspase-dependent apoptotic signaling pathways.
Mechanistically, community and experimental analyses recognized 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 selling α-syn accumulation, which prompts mitochondrial apoptosis by means of BID cleavage, BAX upregulation, and caspase activation. Rescue experiments with ceramide supplementation or α-syn inhibition confirmed the central function of this pathway in artesunate’s anticancer exercise.
By means of built-in computational and experimental analyses, the authors recognized Y313, E340, and N396 as important binding residues throughout the GBA lively website. Web site-directed mutagenesis, significantly the E340R and N396R mutations, considerably impaired artesunate binding and lowered GBA enzymatic exercise, thereby abolishing artesunate’s means to control downstream apoptotic signaling and establishing a direct mechanistic hyperlink between goal engagement and therapeutic exercise.
Collectively, this examine supplies the primary detailed structural and mechanistic characterization of how artesunate straight targets GBA in HCC, figuring out the GBA–ceramide–CTSD–α-syn–BID–BAX signaling axis as a key mediator of mitochondrial apoptosis. These findings set up GBA as a promising therapeutic goal and advance understanding of artesunate’s anticancer exercise, supporting the rational growth of GBA-targeted therapeutic methods for HCC. Whereas the proposed mechanism was validated in HCC cell traces and supported by in vivo research, additional validation in patient-derived organoids and xenograft fashions, along with complete long-term security assessments, shall be important to substantiate its medical relevance and assist translation towards HCC remedy.
Reference
Title of the unique paper: Artesunate straight targets glucosylceramidase to suppress hepatocellular carcinoma proliferation and set off apoptosis
Journal: Genes & Illnesses
Genes & Illnesses is a journal for molecular and translational drugs. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human illnesses. Publication codecs embrace full size analysis article, assessment article, quick communication, correspondence, views, commentary, views on information, and analysis watch.
DOI: https://doi.org/10.1016/j.gendis.2026.102045
# # # # # #
Genes & Illnesses publishes rigorously peer-reviewed and top quality unique articles and authoritative critiques that concentrate on the molecular bases of human illnesses. Emphasis is positioned on hypothesis-driven, mechanistic research related to pathogenesis and/or experimental therapeutics of human illnesses. The journal has worldwide authorship, and a broad scope in fundamental and translational biomedical analysis of molecular biology, molecular genetics, and cell biology, together with however not restricted to cell proliferation and apoptosis, sign transduction, stem cell biology, developmental biology, gene regulation and epigenetics, most cancers biology, immunity and an infection, neuroscience, disease-specific animal fashions, gene and cell-based therapies, and regenerative drugs.
Scopus CiteScore: 10.4 | Affect Issue: 14.6
# # # # # #
Extra info: https://www.keaipublishing.com/en/journals/genes-and-diseases/
Editorial Board: https://www.keaipublishing.com/en/journals/genes-and-diseases/editorial-board/
All points and articles in press can be found online in ScienceDirect (https://www.sciencedirect.com/journal/genes-and-diseases).
Submissions to Genes & Illnesses could also be made utilizing Editorial Manager (https://www.editorialmanager.com/gendis/default.aspx).
Print ISSN: 2352-4820
eISSN: 2352-3042
CN: 50-1221/R
Contact Us: editor@genesndiseases.cn
X (previously twitter): @GenesNDiseases (https://x.com/GenesNDiseases)
# # # # # #
Disclaimer: AAAS and EurekAlert! will not be chargeable for the accuracy of reports releases posted to EurekAlert! by contributing establishments or for using any info by means of the EurekAlert system.
