In MetS, reduced insulin sensitivity in organs, such as the liver, notably decreases tissue glucose uptake and utilization alongside abnormal increases in hepatic glucose output and impaired peripheral glucose utilization, ultimately resulting in abnormal blood glucose levels and impaired glucose tolerance (47). Artemisinin and its derivatives directly improve glycemic parameters and enhance insulin signaling by activating cellular energy sensing. Simultaneously, artemisinin and its derivatives inhibit inflammatory and oxidative stress signaling cascades, thereby blocking chronic inflammation-mediated damage to insulin signaling. These effects contribute to comprehensively improving insulin resistance and restoring glucose homeostasis (Fig. 1).

In db/db mice, artemisinin activates the hepatic PI3K/Akt pathway, upregulating phosphorylated (p-)PI3K, p-Akt, insulin receptor substrate 1 (IRS1) and glucose transporter type 2 (GLUT2) to enhance glucose uptake and suppress gluconeogenesis. Additionally, artemisinin suppresses MAPK signaling by decreasing phosphorylation of p38 mitogen-activated protein kinase (p38), ERK1/2 and JNK, thus alleviating inflammation- and oxidative stress-triggered insulin resistance (48). Artemisinin also inhibits aberrant glycolysis through regulation of the PI3K/Akt/mTOR axis, thereby preserving metabolic homeostasis. In the liver, artemisinin improves insulin sensitivity and reduces ectopic lipid deposition via the AMPK/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. At the cellular level, in hepatocytes, artemisinin potentiates IRS1 activity and PI3K/Akt signaling, promotes glucose transport and glycogen synthesis and suppresses the NF-κB inflammatory pathway, leading to reduced expression levels of pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6, which otherwise disrupt insulin signaling (49,50).

Multiple animal studies have demonstrated that artemisinin-based drugs can considerably reduce fasting and postprandial blood glucose levels (48,51). For instance, artemether and dihydroartemether notably reduced 2 h blood glucose levels in intraperitoneal glucose tolerance and intraperitoneal insulin tolerance tests in a T2DM mouse model. Artemisinin-based drugs also improved serum insulin levels, indicating that these drugs can systemically restore glucose tolerance and insulin sensitivity rather than merely lowering blood glucose levels (21). Artemisinin is hypothesized to induce pancreatic β-cell regeneration to alleviate hyperglycemia, offering a potential strategy to restore pancreatic endocrine function. However, controversy remains regarding this regenerative effect, as multiple studies have failed to replicate α-to-β cell reprogramming in mammalian islet models, highlighting the need for further mechanistic validation (52).

Consistent with the effect of artemether on glycemic control, in a high-fat diet (HFD)-induced obese mouse model, artemether effectively reduced body weight and enhanced systemic insulin sensitivity and glucose tolerance, suggesting that the hypoglycemic effect of artemether reflects a direct improvement in insulin signaling rather than a mere glucose-lowering action (20).

At the systemic level, artemisinin indirectly improves the microenvironment associated with insulin resistance by inhibiting the mTOR pathway, downregulating pro-inflammatory factors (such as TNF-α and IL-6) and alleviating oxidative stress (53,54). Artemisinin also activates the AMPK pathway by upregulating calcium/calmodulin-dependent protein kinase 2, thereby promoting AMPK phosphorylation and consequently enhancing glucose uptake and fatty acid oxidation. By interacting with the Nrf2 antioxidant axis, artemisinin activates downstream antioxidant enzymes, such as superoxide dismutase (SOD), catalase and heme oxygenase-1, thereby mitigating the damage from oxidative stress induced by high glucose or drug treatments, such as amiodarone-triggered insults in human epithelial cell models. Nrf2-knockdown experiments further confirmed the necessity of artemisinin in maintaining insulin signaling (55,56).

Of note, in uveal melanoma cells, artemisinin exerts an opposing effect on the PI3K/Akt/mTOR axis: Artemisinin inhibits the phosphorylation of PI3K, Akt and mTOR, and Akt/mTOR activators can counteract the inhibitory effect of artemisinin on cell migration, demonstrating that artemisinin suppresses cancer cell migration through inhibition of this pathway, highlighting that artemisinin serves as a context-dependent modulator, exerting differential regulatory effects across distinct tissues and pathological states (57).

Given these findings, high-quality clinical studies are needed to clarify the hypoglycemic and insulin-sensitizing efficacy and safety of artemisinin-based drugs in patients with MetS. Artemisinin-based combination regimens should also be explored with metformin and statins to enhance therapeutic efficacy, facilitating the translation of artemisinin derivatives into potential therapeutic agents for MetS.

Dyslipidemia and hepatic steatosis are interrelated and together constitute a vicious cycle of lipid overload-insulin resistance-chronic inflammation-liver damage (58,59). Artemisinin and its derivatives inhibit hepatic lipid synthesis and promote fatty acid oxidation through effects on several pathways, correcting imbalances involving lipid absorption, synthesis and transport. By modulating the gut-liver axis, artemisinin and its derivatives improve lipid profiles while exerting anti-inflammatory and antioxidant effects and restoring insulin signaling pathways, comprehensively ameliorating lipid metabolism disorders and reversing hepatic steatosis (Fig. 2).

In the liver, artemether can reduce the endogenous production of fatty acids and cholesterol by activating the AMPK signaling pathway to inhibit sterol regulatory element-binding protein-1c (SREBP-1c) and its downstream key lipogenic enzymes (acetyl-CoA carboxylase α, fatty acid synthase and stearoyl-CoA desaturase 1), suggesting that artemether can reduce hepatic lipid accumulation by inhibiting excessive lipid synthesis at the source (60). Meanwhile, artesunate notably reduces serum triglyceride (TG) levels and increases high-density lipoprotein cholesterol (HDL-C) in apolipoprotein E-knockout (ApoE⁻/⁻) mice induced by a HFD (61). Regarding the reparative effects on hepatic steatosis, artemether targets the EGFR/heat shock protein 90 (HSP90) complex and upregulates the PPARα/carnitine palmitoyltransferase 1 (CPT1) axis to promote fatty acid β-oxidation, thereby regulating hepatic lipid metabolism and alleviating NASH (60,62,63). Furthermore, artemether can modulate the gut-liver axis, reshape the gut microbiota structure and reduce endotoxemia. By inhibiting the TLR4/NF-κB pathway, artemether blocks activation signals in Kupffer cells, reducing their secretion of pro-inflammatory factors such as TNF-α, IL-1β and IL-6. This action effectively interrupts the amplification of the hepatic inflammatory cascade, ultimately alleviating inflammatory liver damage in NASH (64). Beyond the aforementioned lipid-modulating effects, artemisinin derivatives regulate peroxisome proliferator-activated receptor γ (PPARγ)-mediated lipid metabolic pathways to rebuild the homeostasis of hepatic lipid metabolism and inflammation. Such combined effects ameliorate hepatic lipid deposition and metabolic inflammation synchronously (65). Distinct from these artemether-mediated mechanisms, DHA activates the Nrf2 pathway, inhibits ferroptosis, improves mitochondrial function and indirectly promotes lipid droplet clearance, alleviating hepatic steatosis, inflammation and fibrosis (66).

In atherosclerosis models, artesunate reduces plasma TG, total cholesterol (TC), low-density lipoprotein (LDL) cholesterol (LDL-C), very-LDL-C and arterial lipid deposition through activation of the Krüppel-like factor 2 (KLF2)/Nrf2/transcription factor 7-like 2 (TCF7L2) axis, which enhances LDL receptor-related pathway activity (22). Artemisinin inhibits NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in vascular tissue, reducing caspase-1 and IL-1β expression and decreasing macrophage infiltration and CD68 deposition in arterial plaques. Artemisinin also suppresses NF-κB and other pro-inflammatory signals by regulating the MAPK, PI3K/Akt/mTOR and Nrf2/glutathione (GSH) peroxidase 4 pathways, thereby alleviating vascular chronic inflammation and directly attenuating atherosclerosis (54,61).

Notably, the lipid-regulating effects of artesunate on TC and LDL appear to be model-dependent. In ApoE⁻/⁻ mice fed a HFD, artesunate markedly reduced atherosclerotic plaque formation and serum TG levels, but did not notably alter TC or LDL levels (61). By contrast, in a study using Wistar rats with normal ApoE function, in which acute atherosclerosis was induced by an atherogenic diet (1.25% cholesterol, 15% fat and 0.5% cholic acid) combined with lipopolysaccharide (LPS), artesunate markedly reduced TC and LDL levels, which was comparable to the effect of rosuvastatin (67,68). Similar lipid-lowering and anti-atherosclerotic effects of artesunate have also been reported in HFD-fed ApoE^−/− mice and Western diet-fed rabbits (61,69). This discrepancy may be attributed to the absence of functional ApoE in ApoE⁻/⁻ mice, as ApoE is a required ligand for LDL receptor-mediated lipoprotein clearance, and this genetic deficiency may limit the cholesterol-lowering efficacy of artesunate (61,67). Artemisinin ester may also participate in activating PPARα-related pathways and promoting weight loss and energy expenditure, thereby indirectly improving systemic lipid metabolism (20). Regarding safety, while high doses of artemether may induce gastrointestinal suppression in mice, overall preclinical data indicate no severe adverse effects were observed in this study and the long-term effects of artemether remain uncharacterized as they were not explored in the aforementioned research (21).

Research on NASH models with different etiologies (for example obesity or diabetes mellitus) has not been conducted and clinical translation data are limited (48). Additionally, the regulatory effects of artemether on lipid profiles yield inconsistent results across different animal models and unified efficacy evaluation criteria are lacking (20). Preclinical studies and early-phase clinical trials are needed to test artemisinin-based drugs at low doses over extended periods. These studies should aim to refine the understanding of the cross-regulatory network of the gut-liver axis, standardize research models and evaluation criteria and explore the efficacy of combination therapies with different types of artemisinin derivatives to advance their clinical translation.

Chronic low-grade inflammation and immune homeostasis imbalance are core pathological features of MetS that are primarily manifested by excessive activation of innate immune cells, dysregulation of adaptive immune responses and an imbalance between anti- and pro-inflammatory reactions. These factors continuously exacerbate insulin resistance and disturbances involving glucose and lipid metabolism, forming a vicious cycle of inflammation-metabolism (70–73). Artemisinin and its derivatives correct the inflammation and immune dysregulation associated with MetS by inhibiting pro-inflammatory pathways, activating antioxidant signaling and regulating immune cell homeostasis (Fig. 3).

At the molecular level, DHA suppresses NF-κB activation by blocking upstream signaling and directly binding to NF-κB. This dual inhibition downregulates pro-inflammatory mediators, including TNF-α, IL-1β, IL-6, IL-18, monocyte chemoattractant protein-1 and TGF-β1, as well as adhesion molecules such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Consequently, monocyte adhesion and migration are attenuated and NLRP3 inflammasome activation is restrained. These actions alleviate the chronic low-grade inflammatory immune response in patients with MetS (22,54,74). Furthermore, in ApoE⁻/⁻ mice fed a HFD, artemether inhibited signaling involving the ERK1/2/NF-κB/IL-1β pathway, reduced the macrophage-like phenotypic transformation of vascular smooth muscle cells and decreased NLRP3 and CD68 expression within plaques. Therefore, artemisinin-derived drugs improve underlying metabolic disorders, protect blood vessels and stabilize plaques, highlighting a potential interventional strategy for cardiovascular complications (61).

In an NAFLD model, artemether notably alleviated oxidative stress and inflammatory damage in hepatocytes by activating the Nrf2 antioxidant pathway, thereby promoting Nrf2 nuclear translocation and the expression levels of downstream antioxidant enzymes, including SOD and GSH (25).

In a rat model of T2DM, artemether notably reduced inflammatory markers such as caspase-1 and IL-1β in the salivary glands by inhibiting the NF-κB/NLRP3 pathway, improving oxidative stress and regulating oral dysbiosis. This indicates that the anti-inflammatory effects of artemether are not limited to traditional metabolic organs but can also improve systemic multi-tissue microinflammation (74).

In db/db mice, artemisinin effectively alleviated the inflammatory response associated with glucose and lipid metabolism disorders by inhibiting the MAPK signaling pathway, reducing the phosphorylation of p38, ERK1/2 and JNK and activating the PI3K/Akt pathway (48).

At the cellular immune level, artemisinin-based drugs correct metabolic disorder-induced immune imbalances by reshaping the phenotypic and functional balance of immune cells and regulating the functions of key cells in innate and adaptive immunity. DHA selectively regulates adaptive immune cells by promoting CD4⁺ T cell proliferation and enhancing IFN-γ⁺ CD8⁺ T cell activity, while inhibiting germinal center B cell expansion and reducing the number of circulating plasma cells and antibody production. Therefore, DHA can coordinate immune activation and immune tolerance, thereby preventing excessive immune responses from exacerbating metabolic damage and maintaining immune homeostasis (75). Furthermore, the artemisinin-derived compound β-aminoartemether maleate (SM934) can balance the Th17/Treg cell ratio, promote Treg differentiation and inhibit excessive Th17 cell activation, alleviating chronic low-grade inflammation mediated by immune imbalance (41). Regarding the regulation of innate immune cells, artemether upregulates interferon regulatory factor 4 (IRF4) expression in rodent and non-human primate models, promoting the polarization of macrophages toward the anti-inflammatory M2 phenotype and inhibiting conversion to the pro-inflammatory M1 phenotype. This M2-biased polarization promotes IL-10 and TGF-β secretion to exert its anti-inflammatory and tissue-repairing effects while reducing the release of pro-inflammatory factors, such as TNF-α and IL-1β, alleviating the inflammatory response in vascular restenosis. These observations suggest that artemisinin is not a fixed anti- or pro-inflammatory agent; artemisinin is an immunomodulator capable of dynamically adapting to the tissue microenvironment and pathological state (76).

By contrast, in patients with glioblastoma and a number of tumor models (including models of breast, lung and cervical cancer in vitro, as well as an in vivo breast cancer model), artesunate binds to heme to generate ROS, reversing tumor-associated macrophages from an M2-like, tumor-promoting state toward an M1-like, pro-inflammatory and antitumor state. This phenotypic shift reshapes the immune microenvironment and potentiates antitumor immunity (77,78). In the context of malaria infection, DHA promotes macrophage polarization toward the M1 phenotype by activating NOD-like receptor family pyrin domain-containing 12 (NLRP12), thereby enhancing the host's ability to combat Plasmodium parasites and facilitating parasite clearance (79). Collectively, these observations demonstrate that the immunomodulatory effects of artemisinin derivatives on macrophage polarization are context-dependent. Rather than exerting a fixed anti- or pro-inflammatory effect, artemisinin derivatives function as immunomodulators that differentially regulate macrophage phenotypes depending on the pathological setting, tissue microenvironment and disease context.

However, the poor water solubility and short half-lives of artemisinin derivatives make it difficult to maintain sustained effects for chronic inflammation (80,81). Furthermore, the immunomodulatory effects of artemisinin-based drugs are dose- and microenvironment-dependent. In a malaria model, DHA induced M1 macrophage polarization via an NLRP12-dependent mechanism yet promoted M2 polarization in metabolic inflammation; the critical threshold for this macrophage phenotypic switch remains undefined (79,82). Future studies should focus on developing long-acting sustained-release or targeted delivery systems to meet the needs of chronic interventions. For instance, apigenin-loaded nanoparticles nanocarriers may enhance the macrophage targeting and M2 polarization regulation effects of artemisinin-based drugs (83).

Dysregulation of the gut microbiota-metabolism axis is a key pathogenic mechanism underlying MetS. The gut-microbiota-metabolism axis mediates critical processes such as bile acid reprogramming and tryptophan metabolism through bi-directional pathways, including gut-liver and gut-spleen interactions. Disruption of the gut-microbiota-metabolism axis leads to abnormal metabolites, including secondary bile acids, hydrogen sulfide and dysregulated short-chain fatty acids, which are transmitted via the gut-systemic metabolic axis, severely affecting the host's metabolic and immune balance (84–88). Artemisinin and its derivatives have been reported to modulate this axis, with effects associated with microbiota-dependent pathways. By reshaping the gut microbiota structure, artemisinin and its derivatives optimize the profile of microbial metabolites, regulate the bile acid signaling axis, strengthen the barrier function of the gut-liver axis, alleviate intestinal inflammation and ultimately contribute to the restoration of gut microbiota homeostasis (Fig. 4).

One animal study has shown that artemisinin derivatives are associated with alterations in gut microbiota composition. DHA enhances the α-diversity of the gut microbiota and reshapes the microbial ecosystem structure in mice without causing pathological damage to the liver, kidneys or intestines. DHA increases the abundance of Firmicutes and Spirochaetes while reducing the proportion of Bacteroidetes and Actinobacteria, and these compositional shifts are accompanied by anti-inflammatory and metabolic regulatory effects at the functional level. Metabolic analysis has shown that DHA reduces serum TG levels, with TG content exhibiting a positive correlation with the abundance of Deferribacterota and a negative correlation with the abundance of Spirochaeta, suggesting that the lipid-regulating effects of DHA are partially dependent on gut microbiota remodeling (89). Conversely, artemether increases the abundance of Lactobacillus while reducing the abundance of pathogenic bacteria such as Helicobacter and Prevotella. These changes are associated with AMPK activation, inhibition of the mTOR/NF-κB pathway, reduced pro-inflammatory factor levels and improved insulin resistance and liver and pancreatic tissue damage, suggesting a potential ‘microbiota-metabolism-immunity’ axis that may contribute to the effects of artemisinin-based drugs in the prevention and treatment of T2DM (90). At the molecular level, several pathways have been proposed to link artemisinin-based drugs to the gut microbiota-metabolism axis, with the tryptophan metabolic pathway being among the most studied. Artemether can inhibit the tryptophan-kynurenine metabolic pathway via a heme-dependent mechanism, blocking indoleamine 2,3-dioxygenase 1 (IDO1) activity and reducing kynurenine production. By binding to the heme-binding pocket of IDO1 to inhibit enzyme activity, artemether alleviates kynurenine-mediated inflammation and improves the redox balance of intestinal cells (91). DHA increases the abundance of butyrate-producing bacteria and butyrate levels, whereas artemether increases the content of short-chain fatty acids such as propionate and valerate. One potential mechanism is that these short-chain fatty acids activate G protein-coupled receptor 41/43 (GPR41/43) receptors and the PPARγ pathway, which in turn enhances the expression levels of tight junction proteins, such as zonula occludens-1 and occludin, in the colon and reduces intestinal permeability. This could prevent endotoxins (for example LPS) from entering the bloodstream via the gut and if so, might suppress chronic low-grade inflammation mediated by the gut-metabolic axis and thereby improve insulin resistance (40,90,92).

Within the framework of the gut microbiota-metabolite axis, the gut-liver axis acts as an important signaling conduit that transmits microbiota-derived metabolic signals to the liver, and represents a plausible route through which artemisinin and its derivatives exert hepatoprotective effects. In terms of liver protection, DHA, as a farnesoid X receptor (FXR) agonist, downregulates the expression level of cholesterol 7α-hydroxylase (CYP7A1), which is a key rate-limiting enzyme in the conversion of cholesterol to bile acids, via FXR activation. Through this mechanism, DHA could mitigate the liver damage caused by excessive bile acid accumulation, alleviate hepatic steatosis and holistically protect liver function while controlling obesity (93–97). Together, these pathways could conceivably constitute a microbiota-metabolite-systemic immunity tripartite regulatory network, enabling artemisinin-based drugs to modulate the gut microbiota-metabolite axis.

Circulating metabolites originating from gut microbiota can mediate systemic immune regulation, affecting peripheral immune organs such as the spleen. At the immune regulatory level, artemether can inhibit the activation of pro-inflammatory macrophages, modulate the splenic immune microenvironment and immune cell function and restore host immune homeostasis (98).

Notably, the microbiota-related mechanisms discussed are predominantly correlational and the specific contributions of gut microbiota remodeling to the metabolic effects of artemisinin derivatives remain to be causally established. Causal evidence for microbiota dependence remains tenuous, as direct validation using germ-free animals, antibiotic depletion studies or fecal microbiota transplantation have not yet been reported. Clinical translation is still in its infancy, and the relative merits of distinct artemisinin derivatives in modulating the gut-liver axis remain unclear (99). Future research should prioritize exploratory clinical trials built on the microbiota-metabolite-immune axis to evaluate the long-term impacts of treatment on gut microbiome stability.

Multiple pathways governing the metabolic effects of artemisinin derivatives are fully validated in db/db mice, HFD-induced obesity models and T2DM animals. The hepatic-skeletal muscle PI3K/Akt-GLUT2/GLUT4 axis optimizes glucose metabolism and suppresses gluconeogenesis, as demonstrated in db/db mice and HFD-induced obesity models (48,100,101). AMPK/Nrf2 alleviates oxidative stress-induced insulin resistance, the MAPK/NF-κB pathway breaks the inflammation-insulin resistance cycle and IRF4 reduces systemic inflammation by inducing M2 macrophage polarization, with these mechanisms supported by studies in human retinal pigment epithelial cells, bronchial epithelial cells, Nrf2-knockdown experiments, and rodent and non-human primate models of vascular restenosis (55,56,76). Collectively, these findings constitute direct evidence, as they are derived from both metabolic disease models and mechanistic loss-of-function studies, thereby supporting the classification of these pathways as well-supported.

A second set of pathways are supported by moderate evidence, characterized only in NAFLD, ApoE⁻/⁻ atherosclerotic and other analogous models without systematic verification in MetS, resulting in inconsistent efficacy across species. Hepatic AMPK-SREBP-1c inhibits lipogenesis with variable lipid-lowering effects, as observed in methionine- and choline-deficient (MCD) diet-fed and HFD-fed murine NASH models (60). The gut-liver FXR/CYP7A1 pathway improves hepatic steatosis but lacks long-term validation in obese MetS models, with evidence derived primarily from studies using hepatocellular carcinoma cells and conventional rodent models (93–97). Vascular KLF2/Nrf2/TCF7L2 prevents atherosclerosis with unconfirmed hypoglycemic activity, as demonstrated in ApoE⁻/⁻ mice fed a HFD (22). Hepatic TLR4/NF-κB suppresses inflammation in Kupffer cells within NASH models, yet its link to gut microbiota remains unclear, and PPARα/CPT1 combined with EGFR/HSP90 alleviates fatty liver with poor experimental reproducibility, based on findings in MCD diet-fed mice and oleic acid/palmitic acid-treated HepG2 cells (60,62–64).

The remaining pathways are supported only by indirect speculative evidence, among which certain mechanisms are summarized from malaria and tumor research. Most intestinal-related mechanisms are also grouped in the present review, including the microbiota-metabolism-immune network, the tryptophan-kynurenine-IDO1 cascade and the SCFA-GPR41/43-PPARγ intestinal barrier axis, as these are backed solely by correlational results without causal validation using germ-free animals or fecal microbiota transplantation (89–92). Moreover, the inverse regulation of PI3K/Akt/mTOR detected in melanoma cells highlights the context-dependent pharmacological properties of artemisinin derivatives, indicating that findings from non-metabolic disease models require further validation before extrapolation to metabolic tissue (57).

Among artemisinin derivatives, SM934 represents not only a formulation-optimized derivative with improved aqueous solubility but is also a candidate with preclinical evidence in MetS. In HFD-induced obese mice, SM934 reduced body weight gain, improved glucose tolerance and insulin sensitivity and decreased ectopic lipid deposition in the liver. Mechanistically, SM934 inhibits α-enolase to lower phosphoenolpyruvate (PEP). PEP stabilizes transforming growth factor-β-activated kinase 1 to drive NF-κB-dependent inflammation, SM934 blocks this cascade, curbing macrophage IL-1β secretion and lowering the adipose M1/M2 ratio to relieve obesity-linked meta-inflammation (102). Meanwhile, SM934 activates Nrf2 and represses NF-κB/NLRP3 inflammasome signaling to restore overall immune homeostasis (103). Phase I trials have supported the favorable tolerability profile of SM934 in healthy participants (registered under CTR20160932 and CTR20160933 in the Drug Clinical Trial Registration and Information Disclosure Platform; available a www.chinadrugtrials.org.cn), and a Phase II trial in patients with systemic lupus erythematosus is currently underway (41). In addition, SM934 has demonstrated notable efficacy in various autoimmune and inflammatory disease models, including systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, membranous nephropathy and dry eye syndrome (41).

MetS encompasses a heterogeneous patient population and clinical development should prioritize well-defined subgroups with unmet needs. Polyendocrine metabolic ovarian syndrome (PMOS) represents one of the most advanced clinical targets. A single-arm pilot study in 19 patients with PMOS demonstrated that 40 mg DHA three times daily for 12 weeks normalized menstrual cycles in 63.16% of participants, while also lowering total testosterone and reducing antral follicle count (104). Metabolic dysfunction-associated fatty liver disease (MAFLD) is another priority target. A proof-of-concept trial (NCT07679542) is assessing whether DHA (20 mg three times daily for 12 weeks) reduces liver fat in adults with MAFLD, using MRI-proton density fat fraction-assessed hepatic fat content as the primary endpoint (105). These ongoing proof-of-concept studies in defined patient cohorts represent the initial steps toward a dedicated clinical development pathway for MetS. Candidate clinical endpoints for MetS interventions should include enhanced insulin sensitivity, as assessed by the homeostatic model assessment of insulin resistance, improved glycemic control quantified by glycated hemoglobin A1c, favorable lipid modifications (TG, LDL-C and HDL-C), decreased inflammatory markers (IL-6 and TNF-α) and ultimately, lowered cardiovascular event risk or arrested T2DM progression.

Chronic MetS management requires different dosing strategies from acute malaria treatment. Evidence from a preclinical study suggests that long-term drug exposure, rather than short-term peak concentrations, is the primary driver of artemisinin-related toxicity (106). Rapid oral elimination is therefore associated with a more favorable safety profile compared with delayed release from intramuscular formulations (107). Nevertheless, a 15-year retrospective analysis of artemether-related adverse events from the FDA Adverse Event Reporting System identified hemolytic anemia and hemolysis as the most frequently reported events, with women showing a higher incidence of reproductive-related events, including spontaneous abortion and premature labor. Most adverse events occurred within the first 30 days of artemether administration, with the most affected systems being the hematologic and hepatobiliary systems (108). To date, most clinical trials of artemisinin derivatives have been limited to small-sample Phase I malaria studies. Larger-scale Phase II/III trials are therefore needed to comprehensively evaluate both efficacy and long-term safety in metabolic populations. These findings underscore the need for systematic long-term safety monitoring in future MetS trials, including hematological, hepatic and reproductive assessments.

Patients with MetS frequently receive multiple concomitant medications, including metformin, statins, SGLT2 inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and antihypertensives. Artemisinin and its derivatives are primarily metabolized by cytochrome P450 2B6 (CYP2B6) and cytochrome P450 3A (CYP3A). Artemisinin can induce CYP2B6 and CYP3A4 protein expression, raising the potential for pharmacokinetic interactions with co-administered drugs metabolized by these pathways (109). Reduced enzyme function may lead to subtherapeutic concentrations of the active metabolite DHA, potentially compromising treatment efficacy. Interactions with cardiovascular, antibiotic and antiparasitic agents have been reported, and clinicians should remain vigilant for potential drug-drug interactions when repurposing these agents for chronic metabolic indications (110). Systematic evaluation of interactions with standard MetS medications (including metformin, statins, SGLT2 inhibitors and GLP-1 receptor agonists) are therefore essential before clinical adoption, with careful attention to patient stratification and drug-drug interaction monitoring.

Expanding artemisinin use for non-malarial indications raises legitimate concerns about accelerating antimalarial resistance. Evidence suggests that prolonged or widespread use in malaria-endemic regions could exert selection pressure on Plasmodium parasites (33). To mitigate this risk, non-antimalarial derivatives with altered metabolic profiles, such as SM934, which exhibits distinct immunosuppressive mechanisms independent of the antimalarial activity of SM934, or formulations with shorter exposure windows should be prioritized for MetS indications. Additionally, combination regimens analogous to triple artemisinin combination therapies could be considered to reduce resistance selection pressure in chronic use settings (111). These efforts, combined with robust resistance surveillance, will determine whether artemisinin derivatives can successfully transition from antimalarial agents to viable therapeutics for MetS.