Ferroptosis is a promising strategy for cancer therapy, with numerous inhibitors of its braking axes under investigation as potential drugs. However, few studies have explored the potential of activating the driving axes to induce ferroptosis. Herein, phosphatidylcholine peroxide decorating liposomes (LIPPCPO) are synthesized to induce ferroptosis by targeting divalent metal transporter 1 (DMT1). LIPPCPO is found to boost lysosomal Fe2+ efflux by inducing cysteinylation of lysosomal DMT1, resulting in glutathione peroxidase 4 (GPX4) suppression, glutathione depletion and ferroptosis in breast cancer cells and xenografts. Importantly, LIPPCPO induced ferroptotic cell death is independent of acquired resistance to radiation, chemotherapy, or targeted agents in 11 cancer cell lines. Furthermore, a strong synergistic ferroptosis effect is observed between LIPPCPO and an FDA-approved drug, artesunate, as well as X rays. The formula of LIPPCPO encapsulating artesunate significantly inhibits tumor growth and metastasis and improves the survival rate of breast cancer-bearing female mice. These findings provide a distinct strategy for inducing ferroptosis and highlight the potential of LIPPCPO as a vector to synergize the therapeutic effects of conventional ferroptosis inducers.

OBJECTIVE: Artesunate (ART) is a water-soluble derivative of artemisinin, which has shown anti-inflammatory, anti-tumor, and immunomodulating effects. We aimed to investigate the potential therapeutic effects and mechanisms of ART in metabolic dysfunction-associated steatohepatitis (MASH).
METHODS: The mice were randomly divided into the control group, high-fat, high-cholesterol diet-induced MASH group, and the MASH treated with ART (30 mg/kg once daily) group. Liver enzymes, lipids, and histological features were compared among groups. The molecular mechanisms were studied by transcriptomic and lipidomics analyses of liver tissues.
RESULTS: The mice of the MASH group had significantly increased hepatic fat deposition and inflammation in terms of biochemical indicators and pathological manifestations than the control group. The ART-treated group had improved plasma liver enzymes and hepatic cholesterol, especially at week 4 of intervention (p < 0.05). A total of 513 differentially expressed genes and 59 differentially expressed lipids were identified in the MASH group and the MASH+ART group. Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment test showed that ART regulated glycerolipid metabolism pathway and enhanced fatty acid degradation. Peroxisome proliferator-activated receptor (PPAR)-α acted as a key transcription factor in the treatment of MASH with ART, which was confirmed by cell experiment.
CONCLUSIONS: ART significantly improved fat deposition and inflammatory manifestations in MASH mice, with potential therapeutic effects. The mechanism of artemisinin treatment for MASH may involve extensive regulation of downstream genes by upstream transcription factors, such as PPAR-α, to restore hepatic lipid homeostasis.

METHODS:  A 25-year-old female outpatient presenting with fever and micro-hematuria was treated for urinary tract infection. Her condition worsened over 3 days at home. After experiencing multiple falls caused by leg weakness and mental confusion, she was admitted to a hospital with high fever.
METHODS:  Initial laboratory findings showed hemolytic anemia, pancytopenia, and acute kidney injury, suggesting hemolytic uremic syndrome. However, a detailed fever evaluation revealed her recent return from Afrika. This prompted a malaria test, which confirmed Plasmodium falciparum infection with 80 % parasitemia.
UNASSIGNED:  Despite the quick reduction of parasitemia following treatment with intravenous administered artesunate and oral Artemether-Lumefantrine, her condition worsened, leading to a septic shock. This required renal replacement and kinetic ventilation therapy, as well as blood transfusions due to persistent hemolysis until the laboratory values normalized after 48 days post-admission.
CONCLUSIONS:  The evaluation of fever is often challenging, but most often a detailed patient history is key to early diagnosis and treatment preventing deathly outcomes in severe cases.
UNASSIGNED:  Eine 25-jährige Patientin wurde bei Fieber und Mikrohämaturie wegen des Verdachts auf eine Harnwegsinfektion ambulant behandelt. Ihr Zustand verschlechterte sich jedoch über 3 Tage zunehmend, sodass sie aufgrund von ausgeprägter Schwäche und Verwirrtheit mehrfach stürzte und mit hohem Fieber in ein Krankenhaus eingewiesen wurde.
UNASSIGNED:  Die initialen Laborbefunde zeigten eine hämolytische Anämie, Panzytopenie und ein akutes Nierenversagen, was als ein hämolytisch-urämisches Syndrom diagnostiziert wurde. Erst eine nochmalige detaillierte Anamnese offenbarte eine Reiserückkehr aus Afrika. Ein Malaria-Test zeigte dann eine Infektion mit Plasmodium falciparum mit einer Parasitämie von 80 %.
UNASSIGNED:  Intravenöses Artesunat und oral verabreichtes Artemether-Lumefantrin reduzierten die Parasitämie schnell. Dennoch entwickelte die Patientin infolge der Malaria einen septischen Schock, der eine Nierenersatz- sowie eine kinetische Beatmungstherapie und die Gabe von Bluttransfusionen bei anhaltender Hämolyse – bis zur Normalisierung der Laborwerte nach 48 Tagen – erforderte.
UNASSIGNED:  Bei Fieber ist die Anamnese oft herausfordernd, aber wegweisend, um den wichtigen frühzeitigen Behandlungsbeginn der Malaria nicht zu verzögern und tödliche Ausgänge bei komplizierten Fällen zu verhindern.

Artemisinin is a natural sesquiterpene lactone obtained from the traditional Chinese medicinal herb Artemisia annua L. (qinghao). Artemisinin and its derivatives share an unusual endoperoxide bridge and are extensively used for malaria treatment worldwide. In addition to antimalarial activities, artemisinin and its derivatives have been reported to exhibit promising anticancer effects in recent decades. In this review, we focused on the research progress of artemisinin and its derivatives with potential anticancer activities. The pharmacological effects, potential mechanisms, and clinical trials in cancer therapy of artemisinin and its derivatives were discussed. This review may facilitate the future exploration of artemisinin and its derivatives as effective anticancer agents.

Artesunate (ATS) is considered the most widely employed artemisnin derivative in the treatment of Plasmodium falciparum malaria. However, poor solubility and low bioavailability of ATS limit its further clinical application. Herein, we developed a new strategy based on the exosome (exo) - drug conjugation (EDC) using the milk-derived exosomes for ATS delivery. The Exo-ATS conjugates (EACs) which formed via a facile bio-conjugation of ATS to the exosomal surface, have been demonstrated to be able to not only boost the solubility and bioavailability of ATS but also enable a sustained-release of ATS from exosomes. Maximal improvement of 71.4-fold in the solubility of ATS was attained by EACs. The corresponding entrapment efficiency and drug loading capacities were found to be 90.3% and 73.9% for EACs, respectively. Further, in vivo pharmacokinetics study manifested that maximum 2.6-fold improved bioavailability of ATS was achieved by oral delivery of EACs. Moreover, EACs displayed a distinct sustained-release profile of maximum 36.2-fold prolonged half-life of ATS via intravenous delivery. We reported that for the first time the administration of EACs could be a potential drug delivery strategy aimed at ameliorating the pharmacokinetic profile of ATS based on our encouraging results and hoped that our work opened up a new avenue for the development of EDC delivery system.

UNASSIGNED: Artesunate (ART), a natural compound derived from Artemisia annua, has shown promising clinical potentials in the treatment of various tumors, but the exact mechanism is unclear. Choroidal melanoma (CM) is a major malignant ocular tumor in adults, known for its significant malignancy and poor prognosis, with limited efficacy in current treatments. This study explored the anti-CM effects and mechanisms of ART using a combination of network pharmacology, molecular docking and experimental validation.
UNASSIGNED: Potential targets of ART were screened in PubChem, Swiss Target Prediction and Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database Analysis Platform databases, while target genes related to CM prognosis were selected from Online Mendelian Inheritance in Man (OMIM), GeneCards and DisGeNET databases. The intersection of these two groups of datasets yielded the target genes of ART involved in CM. Protein-protein interaction (PPI) network analysis of the intersecting targets, as well as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, were conducted to identify core targets and critical pathways. Molecular docking methods were performed to predict the binding interactions between ART and core targets. The effects of ART on CM were evaluated through CCK8, colony formation, transwell, as well as flow cytometry assays to detect apoptosis, cell cycle, reactive oxygen species (ROS). Western blot (WB) assays were conducted to investigate the impact of ART on key proteins and pathways associated with CM. Finally, in vivo assays were conducted to further validate the effects of ART on subcutaneous tumors in nude mice.
UNASSIGNED: Research has shown that key pathways and core targets for ART in treating CM were identified through a network pharmacology approach. Molecular docking results verified the strong binding affinity between ART and these core targets. The analysis and predicted results indicated that ART primarily exerted its effects on CM through various tumor-related pathways like apoptosis. The assays in vitro confirmed that ART significantly inhibited the proliferation and migration of CM cells. This was achieved by promoting apoptosis through activation of the p53 signaling pathway, causing cell cycle arrest at the G0/G1 phase by inhibiting the PI3K/AKT/mTOR signaling pathway and increasing the intracellular level of ROS by activating the NRF2/HO-1 signaling pathway. Additionally, the assays in vivo further validated the significant proliferation-inhibitory effect of ART on CM.
UNASSIGNED: This study, making the initial exploration, illustrated through network pharmacology combined with molecular docking and in vitro/in vivo assays, confirmed that ART exerted potential anti-cancer effects on CM by promoting apoptosis, inducing cell cycle arrest and increasing intracellular levels of ROS. These findings suggested that ART held significant therapeutic potential for CM.

A series of organoselenium compounds based on the hybridization of artesunate (ART) scaffolds and Se functionalities (-SeCN and -SeCF3) were synthesized. The redox properties of artesunate-SeCN and artesunate-SeCF3 derivatives were conducted by 2, 2-didiphenyl-1-picrylhydrazyl (DPPH), and the results showed that compounds 2c, 2f and 3e have a good free radical scavenging activity. Their cytotoxicity was evaluated against four types of cancer cell lines, SW480 (human colon adenocarcinoma cells), HCT116 (human colorectal adenocarcinoma cells), HepG2 (human hepatocellular carcinoma cells), MCF-7 (human breast cancer cells). The MTT results showed that compared with ART and 5-FU, compound 2c exhibited potent in vitro antiproliferative activity in SW480, HCT116, and MCF-7 cancer cell lines, and was thus chose for further antitumor mechanism investigation. The antitumor mechanism study revealed that compound 2c induced ferroptosis in HCT116 cells by inhibiting the expression of GPX4 protein, accompanying by the up-regulation of intracellular ROS levels. Mitochondria in HCT116 cells exhibit depolarization of mitochondrial membrane potential (MMP) and ultrastructural changes in morphology, which indicated that 2c resulted in mitochondrial dysfunction and ferroptosis. Moreover, 2c could increase the levels of lipid peroxidation and ferrous ion, which further confirm that compound 2c may exert its antitumor effect through ferroptosis. Overall, these results suggest that the artesunate-Se candidates could provide promising new lead derivatives for further potential anticancer drug development.

Prodrug-based self-assembled nanoparticles (PSNs) with tailored responses to tumor microenvironments show a significant promise for chemodynamic therapy (CDT) by generating highly toxic reactive oxygen species (ROS). However, the insufficient level of intracellular ROS and the limited drug accumulation remain major challenges for further clinical transformation. In this study, the PSNs for the delivery of artesunate (ARS) are demonstrated by designing the pH-responsive ARS-4-hydroxybenzoyl hydrazide (HBZ)-5-amino levulinic acid (ALA) nanoparticles (AHA NPs) with self-supplied ROS for excellent chemotherapy and CDT. The PSNs greatly improved the loading capacity of artesunate and the ROS generation from endoperoxide bridge using the electron withdrawing group attached directly to C10 site of artesunate. The ALA and ARS-HBZ could be released from AHA NPs under the cleavage of hydrazone bonds triggered by the acidic surroundings. Besides, the ALA increased the intracellular level of heme in mitochondria, further promoting the ROS generation and lipid peroxidation with ARS-HBZ for excellent anti-tumor effects. Our study improved the chemotherapy of ARS through the chemical modification, pointing out the potential applications in the clinical fields.

Artesunate (ART) is a derivative of artemisinin and has anti-inflammatory, anti-tumor, and anti-angiogenic properties. Although ART has been implicated in osteoarthritis (OA), the mechanism needs to be further dissected. Here, we explored the effects of ART on the development of OA and the underlying mechanism using destabilization of the medial meniscus (DMM) surgical instability model. Mice with OA were developed using DMM and treated with ART. The pathological morphology of knee joint tissues was examined, and the degeneration of joint cartilage was assessed. Mouse knee chondrocytes were isolated and induced with IL-1β, followed by ART treatment. ART alleviates OA in mice by elevating ubiquitin carboxyl-terminal hydrolase 7 (USP7) expression, and USP7 inhibitor (P22077) treatment mitigated the protective effects of ART on chondrocytes. We also showed that USP7 mediated the deubiquitination of forkhead box protein O1 (FoxO1), while FoxO1 alleviated chondrocyte injury. In addition, FoxO1 promoted metastasis-associated protein MTA1 (MTA1) transcription, and downregulation of MTA1 exacerbated chondrocyte injury. Our study identifies that USP7/FoxO1/MTA1 is a key signaling cascade in the treatment of ART on OA.

Recent research found artesunate could inhibit ocular fibrosis; however, the underlying mechanisms are not fully known. Since the ocular fibroblast is the main effector cell in fibrosis, we hypothesized that artesunate may exert its protective effects by inhibiting the fibroblasts proliferation. TGF-β1-induced ocular fibroblasts and glaucoma filtration surgery (GFS)-treated rabbits were used as ocular fibrotic models. Firstly, we analyzed fibrosis levels by assessing the expression of fibrotic marker proteins, and used Ki67 immunofluorescence, EdU staining, flow cytometry to determine cell cycle status, and SA-β-gal staining to assess cellular senescence levels. Then to predict target genes and pathways of artesunate, we analyzed the differentially expressed genes and enriched pathways through RNA-seq. Western blot and immunohistochemistry were used to detect the pathway-related proteins. Additionally, we validated the dependence of artesunate\'s effects on HO-1 expression through HO-1 siRNA. Moreover, DCFDA and MitoSOX fluorescence staining were used to examine ROS level. We found artesunate significantly inhibits the expression of fibrosis-related proteins, induces cell cycle arrest and cellular senescence. Knocking down HO-1 in fibroblasts with siRNA reverses these regulatory effects of artesunate. Mechanistic studies show that artesunate significantly inhibits the activation of the Cyclin D1/CDK4-pRB pathway, induces an increase in cellular and mitochondrial ROS levels and activates the Nrf2/HO-1 pathway. In conclusion, the present study identifies that artesunate induces HO-1 expression through ROS to activate the antioxidant Nrf2/HO-1 pathway, subsequently inhibits the cell cycle regulation pathway Cyclin D1/CDK4-pRB in an HO-1-dependent way, induces cell cycle arrest and senescence, and thereby resists periorbital fibrosis.