Ferroptosis, an iron-dependent form of regulated cell death, is mechanistically characterized by disrupted iron homeostasis, lipid peroxidation, and compromised antioxidant defense systems. Recent studies have demonstrated that artemisinin and its derivatives, such as dihydroartemisinin and artesunate, exhibit therapeutic potential against lymphatic system malignancies through ferroptosis induction. These compounds exert their antitumor effects by modulating critical regulatory proteins including SLC7A11, GPX4, and STAT3, as well as activating pivotal signaling pathways such as ATF4-CHOP and SREBP2-IPP-GPX4 axes. Notably, synergistic therapeutic effects have been observed when artemisinin derivatives are combined with conventional chemotherapeutic agents or targeted therapies, demonstrating enhanced tumor-suppressive activity and circumvention of drug resistance mechanisms. This review systematically summarizes recent advancements in understanding the ferroptosis-mediated antitumor mechanisms of artemisinin compounds in lymphoid malignancies, with particular emphasis on their molecular targets and clinical translational potential.
Humans ; Ferroptosis/drug effects* ; Artemisinins/therapeutic use* ; Signal Transduction

OBJECTIVES: To investigate the effects of dihydroartemisinin (DHA) combined with doxorubicin (DOX) on proliferation and apoptosis of triple-negative breast cancer cells and explore the underlying molecular mechanism. METHODS: MDA-MB-231 cells were treated with 50, 100 or 150 μmol/L DHA, 0.5 μmol/L DOX, or with 50 μmol/L DHA combined with 0.5 μmol/L DOX. The changes in proliferation and survival of the treated cells were examined with MTT assay and colony-forming assay, and cell apoptosis was analyzed with flow cytometry. Western blotting was performed to detect the changes in protein expression levels of PCNA, cleaved PARP, Bcl-2, Bax, STAT3, p-STAT3, HIF-1α and survivin. RESULTS: The IC₅₀ of DHA was 131.37±29.87 μmol/L in MDA-MB-231 cells. The cells with the combined treatment with DHA and DOX showed significant suppression of cell proliferation. Treatment with DHA alone induced apoptosis of MDA-MB-231 cells in a dose-dependent manner, but the combined treatment produced a much stronger apoptosis-inducing effect than both DHA and DOX alone. DHA at 150 μmol/L significantly inhibited clone formation of MDA-MB-231 cells, markedly reduced cellular expression levels of PCNA, p-STAT3, HIF-1α and survivin proteins, and obviously increased the expression level of cleaved PARP protein and the Bax/Bcl-2 ratio, and the combined treatment further reduced the expression level of p-STAT3 protein and increased the Bax/Bcl-2 ratio. CONCLUSIONS DHA combined with DOX produces significantly enhanced effects for inhibiting cell proliferation and inducing apoptosis in MDA-MB-231 cells possibly as result of DHA-mediated negative regulation of the STAT3/HIF-1α pathway.
Humans ; STAT3 Transcription Factor/metabolism* ; Apoptosis/drug effects* ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Doxorubicin/pharmacology* ; Triple Negative Breast Neoplasms/metabolism* ; Cell Line, Tumor ; Artemisinins/pharmacology* ; Female ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects* ; Survivin

Objective To investigate the anti-inflammatory effect of artemisinin (ART) encapsulated by β-lactoglobulin (BLG) nanoparticles on Winnie spontaneous ulcerative colitis mouse model. Methods BLG-ART nanoparticles were prepared and their effects on the solubility and stability of ART were evaluated. A mouse model of colitis induced by dextran sulfate sodium (DSS) was used to compare the therapeutic effects of artemisinin (ART) administered by direct gavage and artemisinin encapsulated by β-lactoglobulin nanoparticles (BLG-ART) administered by gavage. Winnie mice were randomly divided into blank group, ART group and BLG-ART group. Mice in the ART group were given 50 mg/kg ART by gavage; mice in the BLG-ART group were given the same dose of BLG-ART nanoparticle PBS dispersion by gavage; mice in the blank group were given the same amount of PBS by gavage, for 16 days. The body mass and disease activity index (DAI) of each group of mice were measured. HE staining was used to observe the pathological changes of mouse intestinal tissue, and real-time quantitative PCR was used to detect the mRNA expression levels of TNF-α, interleukin 1β (IL-1β), IL-10 and IL-17 in mouse colon tissue. Results Compared with the ART group and the blank group, the body mass of the BLG-ART group increased and the DAI decreased after 16-day treatment; the crypt structure of the proximal and distal colon regions of the mice recovered; goblet cell loss decreased; neutrophil infiltration decreased and the mRNA expression levels of pro-inflammatory and anti-inflammatory cytokines were significantly down-regulated. Conclusion ART-BLG can alleviate intestinal inflammation in spontaneous ulcerative colitis mice.
Animals ; Mice ; Colitis, Ulcerative/drug therapy* ; Nanospheres ; Inflammation ; Administration, Oral ; Artemisinins ; Disease Models, Animal ; RNA, Messenger

Candida albicans is the most abundant fungal species in oral cavity. As a smart opportunistic pathogen, it increases the virulence by switching its forms from yeasts to hyphae and becomes the major pathogenic agent for oral candidiasis. However, the overuse of current clinical antifungals and lack of new types of drugs highlight the challenges in the antifungal treatments because of the drug resistance and side effects. Anti-virulence strategy is proved as a practical way to develop new types of anti-infective drugs. Here, seven artemisinins, including artemisinin, dihydroartemisinin, artemisinic acid, dihydroartemisinic acid, artesunate, artemether and arteether, were employed to target at the hyphal development, the most important virulence factor of C. albicans. Artemisinins failed to affect the growth, but significantly inhibited the hyphal development of C. albicans, including the clinical azole resistant isolates, and reduced their damage to oral epithelial cells, while arteether showed the strongest activities. The transcriptome suggested that arteether could affect the energy metabolism of C. albicans. Seven artemisinins were then proved to significantly inhibit the productions of ATP and cAMP, while reduced the hyphal inhibition on RAS1 overexpression strain indicating that artemisinins regulated the Ras1-cAMP-Efg1 pathway to inhibit the hyphal development. Importantly, arteether significantly inhibited the fungal burden and infections with no systemic toxicity in the murine oropharyngeal candidiasis models in vivo caused by both fluconazole sensitive and resistant strains. Our results for the first time indicated that artemisinins can be potential antifungal compounds against C. albicans infections by targeting at its hyphal development.
Animals ; Mice ; Candida albicans ; Candidiasis, Oral/drug therapy* ; Antifungal Agents/pharmacology* ; Hyphae ; Artemisinins/pharmacology*

Artemisinins/therapeutic use* ; Antiviral Agents/therapeutic use*

Malaria, one of the major global public health events, is a leading cause of mortality and morbidity among children and adults in tropical and subtropical regions(mainly in sub-Saharan Africa), threatening human health. It is well known that malaria can cause various complications including anemia, blackwater fever, cerebral malaria, and kidney damage. Conventionally, cardiac involvement has not been listed as a common reason affecting morbidity and mortality of malaria, which may be related to ignored cases or insufficient diagnosis. However, the serious clinical consequences such as acute coronary syndrome, heart failure, and malignant arrhythmia caused by malaria have aroused great concern. At present, antimalarials are commonly used for treating malaria in clinical practice. However, inappropriate medication can increase the risk of cardiovascular diseases and cause severe consequences. This review summarized the research advances in the cardiovascular complications including acute myocardial infarction, arrhythmia, hypertension, heart failure, and myocarditis in malaria. The possible mechanisms of cardiovascular diseases caused by malaria were systematically expounded from the hypotheses of cell adhesion, inflammation and cytokines, myocardial apoptosis induced by plasmodium toxin, cardiac injury secondary to acute renal failure, and thrombosis. Furthermore, the effects of quinolines, nucleoprotein synthesis inhibitors, and artemisinin and its derivatives on cardiac structure and function were summarized. Compared with the cardiac toxicity of quinolines in antimalarial therapy, the adverse effects of artemisinin-derived drugs on heart have not been reported in clinical studies. More importantly, the artemisinin-derived drugs demonstrate favorable application prospects in the prevention and treatment of cardiovascular diseases, and are expected to play a role in the treatment of malaria patients with cardiovascular diseases. This review provides reference for the prevention and treatment of malaria-related cardiovascular complications as well as the safe application of antimalarials.
Child ; Adult ; Humans ; Antimalarials/pharmacology* ; Cardiovascular Diseases/drug therapy* ; Artemisinins/pharmacology* ; Quinolines ; Malaria, Cerebral/drug therapy* ; Heart Failure/drug therapy* ; Arrhythmias, Cardiac/drug therapy*

Microbial transformation is an efficient enzymatic approach for the structural modification of exogenous compounds to obtain derivatives. Compared with traditional chemical synthesis, the microbial transformation has in fact the undoubtable advantages of strong region-and stereo-selectivity, and a low environmental and economic impact on the production process, which can achieve the reactions challenging to chemical synthesis. Because microbes are equipped with a broad-spectrum of enzymes and therefore can metabolize various substrates, they are not only a significant route for obtaining novel active derivatives, but also an effective tool for mimicking mammal metabolism in vitro. Artemisinin, a sesquiterpene with a peroxy-bridged structure serving as the main active functional group, is a famous antimalarial agent discovered from Artemisia annua L. Some sesquiterpenoids, such as dihydroartemisinin, artemether, and arteether, have been developed on the basis of artemisinin, which have been successfully marketed and become the first-line antimalarial drugs recommended by WHO. As revealed by pharmacological studies, artemisinin and its derivatives have exhibited extensive biological activities, including antimalarial, antitumor, antiviral, anti-inflammatory, and immunomodulatory. As an efficient approach for structural modification, microbial transformation of artemisinin and its derivatives is an increasingly popular strategy that attracts considerable attention recently, and numerous novel derivatives have been discovered. Herein, this paper reviewed the microbial transformation of artemisinin and its artemisinin, including microbial strains, culture conditions, product isolation and yield, and biological activities, and summarized the advances in microbial transformation in obtaining active derivatives of artemisinin and the simulation of in vivo metabolism of drugs.
Animals ; Antimalarials/pharmacology* ; Antiviral Agents ; Artemether ; Artemisinins ; Mammals

OBJECTIVE: To investigate the potential value and its mechanism of dihydroartemisinin (DHA) in the treatment of acute myeloid leukemia (AML). METHODS: The effect of DHA on the viability of AML cells was detected by CCK-8 assay. The effect of DHA on intracellular oxidation-reduction state was detected by fluorescence probe staining and flow cytometry. Western blot, adenovirus transfection, and laser confocal analysis were used to analyze the effect of DHA on autophagy. The small molecule inhibitors were used to further elucidate the possible mechanism of DHA-induced AML cell death. RESULTS: DHA could inhibit the viability of HL-60 and Kasumi-1 cell lines, and significantly increase the level of intracellular oxidative stress. When treated with 10 μmol/L DHA, reactive oxygen species (ROS) in HL-60 cells and Kasumi-1 cells was increased to 2.6 times and 2.0 times, respectively. In addition, the expression of autophagy-related proteins were up-regulated in DHA-treated AML cells, together with the increase of intracellular autophagy flux and activation of autophagy. Furthermore, autophagy inhibitors reduced DHA-induced cell death, and inhibited the level of oxidative stress by scavenging intracellular free radicals, thus inhibiting autophagy and restoring cell viability. CONCLUSION DHA can activate autophagic cell death of AML by inducing oxidative stress.
Apoptosis ; Artemisinins/pharmacology* ; Autophagic Cell Death ; Autophagy ; Humans ; Leukemia, Myeloid, Acute ; Oxidative Stress

OBJECTIVE: To investigate the effect of dihydroartemisinin (DHA) combined with arsenic trioxide (ATO) on the viability and apoptosis of acute myeloid leukemia (AML) FLT3-ITD mutant cell line MOLM13 and its mechanism. METHODS: MOLM13 cells were treated with DHA or ATO alone or in combination. The viability of MOLM13 cells was detected by CCK-8 assay, cell proliferation was observed by colony formation assay, cell apoptosis and reactive oxygen species (ROS) level were measured by flow cytometry, and the expression levels of proteins related to apoptosis were detected by Western blot. RESULTS: Compared with the control group, treatment with DHA and ATO alone or in combination could inhibit cell proliferation, activate ROS formation, and finally induce cell apoptosis. DHA in combination with ATO produced a synergistic effect. Western blot analysis showed that DHA combined with ATO could significantly upregulate the level of c-PARP and activate apoptosis via inhibition of Mcl-1 and FLT3-ITD. CONCLUSION DHA combined with ATO induces the apoptosis of FLT3-ITD AML cell line MOLM13 by inhibiting Mcl-1 pathway and activating FLT3-ITD protein degradation.
Apoptosis ; Arsenic Trioxide/therapeutic use* ; Artemisinins/therapeutic use* ; Cell Line, Tumor ; Humans ; Leukemia, Myeloid, Acute/drug therapy* ; Myeloid Cell Leukemia Sequence 1 Protein ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use* ; Reactive Oxygen Species/therapeutic use* ; Sincalide/therapeutic use* ; fms-Like Tyrosine Kinase 3

OBJECTIVE: To investigate the potential antitumor effect and its mechanism of dihydroartemisinin (DHA) on diffuse large B-cell lymphoma (DLBCL). METHODS: OCI-Ly7 cells were respectively treated with different concentrations of DHA (0, 12.5, 25, 50 and 100 μmol/L) , CCK-8 was used to detect the cells viability. Subsequently, OCI-Ly7 cells were divided into 5 groups : DHA 0,25,50,100 μmol / L and DHA (100 μmol / L) + Colivelin (STAT3 activator). Aldehyde dehydrogenase (ALDH) positive cells were sorted by flow cytometry, the sphere-forming ability of stem cells was detected. Transwell assay and scratch test were used to analyze the invasion and migration of cells. Western blot was used to detect the expression of migration and invasion-related proteins, as well as the phosphorylation levels of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3(STAT3). RESULTS: DHA induced obvious cytotoxicity to OCI-Ly7 cells. Compared with the control group, the stem cell-like properties, invasion and migration of OCI-Ly7 were significantly inhibited in DHA 50 μmol/L group and 100 μmol/L group, while the phosphorylation levels of JAK2 and STAT3 were significantly reduced. There was no significant difference in DHA 25 μmol/L group compared with the control group. Treated with Colivelin, the inhibition of DHA on OCI-Ly7 stem cell-like properties, invasion and migration was significantly reversed, and the expression of p-STAT3 was significantly up-regulated. CONCLUSION DHA has antitumor effect on DLBCL, and its mechanism may be through inhibiting the activation of JAK2/STAT3 pathway to inhibit the stem cell-like properties, invasion and migration of DLBCL cells.
Aldehyde Dehydrogenase/pharmacology* ; Antineoplastic Agents/therapeutic use* ; Artemisinins/pharmacology* ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Janus Kinase 2 ; Lymphoma, Large B-Cell, Diffuse/pathology* ; STAT3 Transcription Factor/metabolism* ; Signal Transduction ; Sincalide/pharmacology*