Ubiquitous environmental nano-plastics (NPs) can enter organisms via multiple pathways, posing potential health risks; however, the adverse effects of gestational polystyrene NPs (PS-NPs) exposure on adult offspring reproductive function and underlying mechanisms remain unclear. The adverse outcome pathway (AOP) framework models toxic events from molecular to organismal levels. This study employed multi-omics analysis to construct a putative partial-AOP network, revealing insights into the mechanism of intergenerational reproductive impairment of PS-NPs in adult offspring. Gestational PS-NPs exposure induced testicular structural damage and abnormal spermatogenesis in adult male offspring. The testicular transcriptomic and serum metabolomic data integration, validation and the omics-anchored AOP network construction highlighted four molecular events in adult male offspring following gestational PS-NPs exposure: increased arachidonic acid release, elevated reactive oxygen species levels, increased palmitic acid levels, and decreased lysophosphatidyl choline levels. These molecular events might be implicated in a series of cellular key events (KEs), ranging from cellular damage and impaired proliferation to cell death. These cellular KEs could contribute to testicular cell reduction and organ-level KEs-testicular injury, reduced androgen secretion, and impaired spermatogenesis-culminating in the adverse outcome of reproductive dysfunction. This putative network characterizes the molecular and histopathological landscape of reproductive impairment in adult male offspring associated with gestational PS-NPs exposure, and provides clues for elucidating the intergenerational toxicity mechanisms of PS-NPs.

Parkinson's disease (PD) is often accompanied by symptoms of gastric dysmotility, such as gastroparesis. Gastroparesis not only seriously affects the life quality of PD patients, but also causes fluctuations in drug absorption rate, exacerbating the motor symptoms of PD. The previous studies of our laboratory have shown that PD model rats also exhibit gastroparesis, with increased pro-inflammatory cytokines in the gastric muscularis. The markers of related neurons were abnormal. Additionally, the contractile protein markers, as well as their transcriptional regulators, were reduced in smooth muscle cells (SMCs). Continuous gastric feeding of Qizhiweitong particles (QZWT) for seven days improved gastric motility in PD rats with gastroparesis by suppressing inflammation. However, whether QZWT can restore neurons in the gastric muscularis and the differentiated phenotype of SMCs remains to be further investigated. In this study, we detected expressions of neuronal markers in the gastric muscularis and contractile markers of SMCs by immunofluorescence staining, Western blotting, and real-time quantitative PCR, and observed the ultrastructure of SMCs by transmission electron microscopy techniques, aiming to explore the potential mechanisms underlying the improvement effect of QZWT on gastric dysmotility in PD rats and provide new ideas for the treatment of PD gastroparesis. Our results showed that after QZWT administration, there was no change in neuronal markers tyrosine hydroxylase, choline acetyltransferase, and neuronal nitric oxide synthase in the muscular layer of gastric corpus of the PD gastroparesis rats. However, compared to the PD rats, the protein and mRNA expression levels of myosin heavy chain 11 and myosin light chain 20 were significantly up-regulated in the smooth muscle layer of gastric corpus of PD rats with QZWT treatment. Furthermore, the protein and mRNA expression levels of serum response factor (SRF), which regulates the transcription of SMC contractile protein genes, as well as the mRNA level of the transcription related cofactor myocardin (MYOCD), were significantly up-regulated. In addition, the ultrastructure feature of gastric corpus showed that the morphology of SMCs in the PD rats with QZWT treatment was improved, displaying clear dense patches and dense bodies. The vacuoles in the SMCs disappeared. These results suggest that QZWT treatment up-regulates the expression of SRF and MYOCD, which may be associated with its effect of inhibiting inflammation, and further increases the expression of contractile proteins and restores the morphology of the SMCs, promoting gastric smooth muscle contractions in PD gastroparesis rats, thereby leading to improved gastric motility.

Decabromodiphenyl ethane (DBDPE), as the novel brominated flame retardant, has been frequently detected in aquatic environments worldwide and has been confirmed to be harmful to aquatic organisms. Previous studies have mostly inferred potential damage to specific organs based on abnormal behaviors in zebrafish, but the multi-organ cross-toxicity of DBDPE and its underlying mechanisms remain to be elucidated. In this study, zebrafish (Danio rerio) embryos were exposed to DBDPE at concentrations of 5, 50, and 500 μg/L for 120 h. The results showed that DBDPE impaired embryonic development, causing cardiotoxicity, neurotoxicity, and visual toxicity. DBDPE induced excessive production of reactive oxygen species (ROS), accumulation of malondialdehyde (MDA), and depletion of glutathione (GSH), which in turn triggered phosphatidylethanolamine (PE) accumulation and ferroptosis-related proteins (ceruloplasmin, heme oxygenase 1, and autophagy-related protein 5) downregulation, accompanied by cardiac developmental abnormalities such as pericardial edema, increased heart rate, and prolonged sinoatrial-atrioventricular (SV-BA) distance. Beyond its cardiac effects, DBDPE exposure induced distinct neurotoxicity, including anxiety and aggression. Mechanistically, DBDPE directly interfered with lysophosphatidylcholine (LysoPC) metabolism and disrupted the normal localization of metabotropic glutamate receptor 5 (mGluR5), leading to neurobehavioral abnormalities. In addition, the phenomenon of ocular protrusion may be related to abnormal expression of retinol dehydrogenase 12 (RDH12) and glucuronosyltransferase (UGT1B2), key factors in retinol metabolism. This study firstly showed that DBDPE's multi-organ developmental toxicity is driven by an interconnected metabolic-protein network, which not only significantly advances the understanding of the complex toxic mechanisms of DBDPE, but also lays a solid scientific foundation for accurate environmental risk assessment and early health warning of such emerging pollutants.

OBJECTIVE:Global growth hormone receptor knockout (GHR-/-) extends lifespan but also causes adverse effects. As a key target of growth hormone (GH), adipose tissue may mediate aging, though the underlying mechanisms remain unclear. We investigated how adipose-specific GHR ablation influences multisystem aging, with a focus on metabolic health and cognitive function. METHODS:We generated adipose-specific GHR knockout (Ad-GHRKO) mice and assessed healthspan parameters including cognitive function, musculoskeletal integrity and metabolic profiles. Adipose tissue remodelling and inflammation were examined by histology and protein analysis. Subcutaneous white adipose transcriptomics identified gene expression changes. The role of the AMPK-SIRT1-Ac-PPARγ pathway in metabolic elasticity and aging was elucidated by Western blot and in vitro assays. RESULTS:Ad-GHRKO mice exhibited extended healthspan, with enhanced cognitive performance, improved muscle strength and bone mass and a lifespan increase trend. Mechanistically, GHR ablation remodelled adipose tissue, reducing age-related lipid redistribution, restoring glucose homeostasis and creating a low-inflammation, high-plasticity depot. This reprogramming boosted systemic metabolic elasticity primarily via AMPK-SIRT1-Ac-PPARγ activation. AMPK inhibition abolished benefits, confirming its pivotal role. CONCLUSION:Our findings identify adipose-specific GH signalling antagonism as a regulatory switch that recalibrates the local balance between GH and IGF-1 actions, thereby reprogramming adipose tissue to promote coordinated systemin metabolic resilience during aging. This tissue-targeted strategy circumvents the developmental and endocrine limitations associated with global GH/IGF-1 suppression. Rather than merely extending lifespan, adipose-specific GHR ablation supports healthier aging by preserving metabolic homeostasis, maintaining multisystem functional integrity and reducing age-associated inflammatory and fibrotic remodelling. Collectively, these results highlight a potentially translatable approach for mitigating age-related metabolic and cognitive decline.

This review provides an in-depth analysis of the key regulatory pathways involving endothelin-1 (ET-1) and its receptors in the progression of ovarian cancer. As one of the most common malignancies affecting the female reproductive system, ovarian cancer exhibits complex pathogenesis and limited treatment options, making it a critical focus in oncology research. ET-1, a potent vasoconstrictive peptide with diverse biological functions, is implicated not only in normal physiological processes but also plays a pivotal role in ovarian cancer initiation, progression, invasion, metastasis, and chemoresistance. The article begins by outlining the fundamental features of ovarian cancer, including its major histopathological subtypes, incidence, and mortality rates. It then examines the structural and functional aspects of ET-1 and its receptors, elucidating their multifaceted roles in ovarian cancer pathobiology, such as promoting tumor cell proliferation, inhibiting apoptosis, inducing angiogenesis, facilitating epithelial–mesenchymal transition (EMT), mediating chemotherapy resistance, and enhancing cell adhesion and invasion. Furthermore, the review highlights the therapeutic potential of targeting ET-1 signaling pathways, encompassing strategies such as inhibition of ET synthesis, receptor antagonism, and combination therapies. Finally, it discusses future research directions aimed at advancing precision medicine approaches for ovarian cancer treatment.

Effective therapies for liver fibrosis are lacking. The RNA-binding protein Lin28A is upregulated in human cirrhotic and mouse fibrotic livers, where it localizes to activated hepatic stellate cells (HSCs). HSCs-specific overexpression of Lin28A worsened carbon tetrachloride (CCl4)-induced fibrosis in mice. In LX-2 and primary mouse HSCs, Lin28A knockdown suppressed activation and induced hallmarks of ferroptosis, including mitochondrial damage, lipid peroxidation, and glutathione depletion. Mechanistically, Lin28A repressed the maturation of let-7 microRNAs, leading to increased expression of its target, high-mobility group AT-hook 2 (HMGA2). HMGA2, alongside hypoxia-inducible factor-1α (HIF-1α), contributed to the downregulation of the ferroptosis defense proteins SLC7A11 and GPX4. Notably, the anti-fibrotic effects of the Lin28A inhibitor C1632 were dependent on ferroptosis induction, as co-treatment with ferrostatin-1 reversed its impact on HSCS activation and death. In vivo, C1632 treatment alleviated CCl4-induced liver fibrosis. These results identify Lin28A as a regulator of HSCS ferroptosis and a potential target for anti-fibrotic therapy.

Cervical cancer (CC) is the most common gynecological malignancy and is strongly linked to human papillomavirus (HPV) infection. Currently, immune checkpoint blockade therapy has shown limited clinical benefits for CC, highlighting the need to find more effective therapeutic targets. LILRB4, a member of the leukocyte immunoglobulin-like receptor superfamily, is considered a key mediator of cancer immunosuppression. However, its role in the CC immune microenvironment remains unclear. Here, LILRB4 expression was upregulated in CC tissues, and high expression levels were positively associated with advanced disease and immunosuppressive genes in tumors. In an immunocompetent mouse model, LILRB4 expression in CC tumors increased with tumor growth, whereas blocking LILRB4 reduced tumor growth. Flow cytometry analysis revealed that blockade of LILRB4 reduced CD8+ T-cell exhaustion within tumors. Additionally, blockade of LILRB4 decreased the number of tumor‑infiltrating myeloid cells (TIMs), including myeloid‑derived suppressor cells (MDSCs) and M2 tumor‑associated macrophages (M2‑TAMs). Cell coculture experiments demonstrated that blockade of LILRB4 prevented CD8+ T-cell exhaustion by reducing the numbers of MDSCs and TAMs. Furthermore, HPV16 upregulated ApoE expression through transcriptional regulation, and LILRB4 mediated the suppression of CD8+ T cells by ApoE. Overall, the HPV16/ApoE/LILRB4 axis induced TIM-mediated suppression of CD8+ T cells, creating an immunosuppressive microenvironment that promoted CC progression.

Dietary ingestion of nanoplastics through contaminated food and drinking water has become a pressing human health concern. Despite this pressing health concern, the developmental reproductive impacts of gestational nanoplastics exposure on female offspring remains poorly characterized. Using ICR mouse models subjected to prenatal exposure to 60-nm polystyrene nanoplastics (PS-NPs: 5, 50, or 500 mg/kg/day), this study demonstrated that maternal perinatal PS-NPs exposure significantly disrupted ovarian development, induced precocious puberty, and caused ovarian follicular depletion in female offspring, evidenced by reduced ovarian coefficients, advanced vaginal opening, depleted primordial follicles, and elevated atretic follicles. Mechanistically, ovarian development dysregulations arise from suppressed FOXL2-CYP19A1 signaling and downregulated RSPO1/WNT4/β-catenin pathways, while precocious puberty is driven by earlier elevation of serum GnRH levels and hypothalamic reprogramming. Quantitative proteomics reveals dose-dependent pathway alterations: low-dose PS-NPs dysregulate immune/estrogen responses, whereas high-dose exposure causes steroidogenic disruption and apoptotic dysregulation. Serum hormone profiling showed markedly reduced AMH/E2 and elevated LH, corroborated by transcriptional downregulation of key receptors (amh, ERα, and AR). These findings highlight a potential risk to fetal ovarian development posed by maternal nanoplastics exposure, urging the incorporation of developmental and reproductive toxicity into the comprehensive risk assessment of human exposure to micro/nano-plastics.

ABSTRACT Background Dopamine (DA) exerts complex concentration‐dependent effects on gastrointestinal motility. Although its inhibitory action through D2‐like receptors is well‐established, the mechanisms underlying its excitatory effects remain elusive. This study investigates the facilitatory effect of low‐concentration DA on gastric corpus motility and identifies the specific receptor and pathway involved. Methods Gastric motility recording, enzyme‐linked immunosorbent assay (ELISA), double‐labeled immunofluorescence, western blotting, M 2 /M 3 knockout mice, and D 5 R transgenic mice were used in this study. Results In isolated rat gastric strips, low‐dose DA (10–100 nM) enhanced spontaneous contractions, an effect mimicked by the D1‐like receptor agonist SKF38393 but not by the D2‐like agonist quinpirole. Immunofluorescence revealed that both D 1 R and D 5 R are co‐expressed with cholinergic neurons in the myenteric plexus. The prokinetic effects of DA and SKF38393 were abolished by tetrodotoxin or atropine, indicating neural and cholinergic dependence. Critically, using humanized D 5 R transgenic mice, gain‐of‐function (D 5 S390G ) and loss‐of‐function (D 5 F173L ) mutants, we established D 5 R as indispensable for the excitatory response: D 5 S390G mice showed enhanced contractility to DA and SKF38393, whereas D 5 F173L mice exhibited no response. Furthermore, in M 2 /M 3 muscarinic receptor knockout mice, DA and SKF38393 failed to enhance contractions, confirming the dependence on acetylcholine‐mediated smooth muscle activation. Conclusion These results identify a novel neurogenic pathway in which low‐concentration DA activates neuronal D 5 R on cholinergic enteric neurons, leading to acetylcholine release and M 2 /M 3 receptor‐mediated contraction of gastric smooth muscle. Our findings establish D 5 R as a critical mediator of dopamine‐induced gastric excitation in ex vivo preparations. Although the present study does not include in vivo experiments, these mechanistic insights suggest that D 5 R may represent a potential therapeutic target for gastroparesis and related motility disorders, warranting further validation in in vivo models.

Dopamine (DA) plays an important role in regulating gastrointestinal (GI) motility; however, the specific contribution of colonic dopamine D2 receptor (D2 receptor) remains incompletely understood. This study investigated the role of D2 receptor in colonic motility using pharmacological approaches in D2 receptor-deficient (D2R-/-) mice and a 6-hydroxydopamine (6-OHDA) rats model of Parkinson's disease (PD). In wild-type mice, low-dose DA and D2 receptor agonist quinpirole enhanced colonic spontaneous contractility. This pro-contractile effect was completely abolished by tetrodotoxin, indicating a neuron-dependent mechanism. D2R-/- mice exhibited prolonged colonic transit time, reduced spontaneous contractility, and upregulation of somatostatin (SST) and its receptor somatostatin receptor 2 (SST2 receptor). Moreover, the excitatory effect of quinpirole was prevented by a selective SST2 receptor antagonist (CYN154806) but not by inhibitors of cholinergic or nitrergic pathways, which identified the SST-SST2 receptor pathway as the key downstream mediator of D2 receptor. Furthermore, exogenous octreotide (a synthetic SST analogue) directly inhibited spontaneous contractility in colonic strips via myogenic SST2 receptor, a process blocked by CYN154806 but unaffected by tetrodotoxin. In 6-OHDA rats with colonic hypomotility, colonic SST and SST2 receptor were upregulated, while the excitatory response to quinpirole was preserved and remained sensitive to SST2 receptor blockade. In conclusion, D2 receptor is critical for maintaining colonic motility by modulating inhibitory SST-expressing enteric neurons, thereby suppressing myogenic SST2 receptor signalling. Moreover, the observed upregulation of this pathway in 6-OHDA rats suggests that a disrupted D2 receptor-SST-SST2 receptor axis may contribute to the colonic dysfunction in PD.

Polystyrene nanoplastics (PS-NPs) are extensively present in the environment. Population studies have confirmed the presence of micro- and nanoplastics in human blood and placental tissues, and animal experiments found PS-NPs had potential developmental and reproductive toxicity. However, the continuous effects of prenatal PS-NPs exposure on testicular differentiation and development in offspring from embryo to adult are not clear. Therefore, this study aimed to investigate potential toxicity of prenatal exposure to PS-NPs on testicular development in offspring mice from embryonic day 11.5 (E11.5) to postnatal day 90 (PND90). Results showed that PS-NPs led to limited growth during embryonic period. After birth, PS-NPs caused catch-up growth, early onset of puberty, and reduced male reproductive capacity in adult mice. Moreover, we conducted further research on the possible mechanisms and found that PS-NPs might cause male reproductive developmental toxicity by inhibiting mRNA levels of genes related to testicular differentiation and development (Sry/Sox9/Fgf9, AMH, Dmrt1) from embryo to adulthood, which might have relationships with reduced number of Sertoli cells in the seminiferous tubules. Also, PS-NPs interfered with testosterone synthesis and disturbed lipid metabolism according to our proteomic analysis. This research may provide more evidence to the possible male developmental and reproductive toxicity induced by PS-NPs.

Introduction:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the rapid loss of motor neurons. Given the significant global economic impact of ALS, effective preventive measures are urgently needed to reduce the incidence of this devastating disease. Recent meta-analyses have explored potential links between environmental factors, biomarkers, and ALS occurrence. However, the findings of these studies have been inconsistent and controversial. Therefore, we present a comprehensive umbrella review of recent meta-analyses to systematically summarize the available epidemiological evidence and evaluate its credibility. Methods:A systematic search was conducted in PubMed and Embase from inception until 01 October 2024, to identify meta-analyses of observational studies examining associations between environmental risk factors, protective factors, biomarkers, and ALS susceptibility. For each meta-analysis, summary effect estimates, 95% confidence intervals (CIs), 95% prediction intervals, study heterogeneity, small study effects, and excess significance biases were calculated independently by two investigators. The methodological quality was evaluated using the AMSTAR 2 criteria. The strength of the epidemiological evidence was categorized into five levels based on predefined criteria. Results:Out of 1,902 articles identified, 43 met the inclusion criteria, resulting in 103 included meta-analyses. These analyses covered 46 environmental risk and protective factors (344,597 cases, 71,415,574 population) and 57 cerebrospinal fluid (CSF) and serum biomarkers (30,941 cases, 2,180,797 population). The evidence was classified as convincing (Class I) for the regular use of antihypertensive drugs (OR: 0.85, 95% CI: 0.81-0.88) and highly suggestive (Class II) for premorbid body mass index (OR: 0.97, 95% CI: 0.95 to 0.98), trauma (OR: 1.51, 95% CI: 1.32 to 1.73), CSF NFL levels (SMD: 2.06, 95% CI: 1.61 to 2.51), serum NFL levels (SMD: 1.57, 95% CI: 1.29 to 1.85), ferritin levels (SMD: 0.66, 95% CI: 0.50 to 0.83), and uric acid levels (SMD: -0.72; 95% CI: -0.98 to -0.46). Discussion:This umbrella review offers new insights into the epidemiological evidence regarding the associations between environmental factors, biomarkers, and ALS susceptibility. We aim for our study to enhance the understanding of the roles of environmental factors and biomarkers in ALS occurrence and assist clinicians in developing evidence-based prevention and control strategies.

OBJECTIVES:Increasing epidemiological evidence has reported that various factors are associated with migraine risk and subtypes. Nevertheless, definitive conclusions regarding whether the putative modifiable risk factors are causally related to the pathogenesis of migraine have not been drawn. METHODS:Using single-nucleotide polymorphisms as instrumental variables, we conducted a two-sample Mendelian randomization (MR) analysis to investigate the causal effects of 38 modifiable factors, including dietary nutrients, lifestyle factors, cardiometabolic diseases, and associated traits, as well as reproductive characteristics and sex hormones, on the risk of migraine, migraine with aura (MA), and migraine without aura (MO). Subsequently, meta-analyses were performed to combine causal estimates from two independent genome-wide association studies. RESULTS:In the combined findings with multiple test correction, genetically predicted higher alcohol intake frequency (odds ratio [OR]: 1.25; 95% confidence interval [CI]: 1.12-1.40), lifetime smoking index (OR: 1.24; 95% CI: 1.08-1.42), insomnia (OR: 1.20; 95% CI: 1.17-1.24), long sleep duration (OR: 1.26; 95% CI: 1.07-1.50), and hypertension (OR: 1.76; 95% CI: 1.47-2.11) were causally linked to migraine incidence. Subgroup analyses revealed higher carbohydrate and sugar intake, alcohol consumption frequency, lifetime smoking index, insomnia, and hypertension causally increased susceptibility to MA, while later age at first birth (AFB) had a protective effect on MA risk. Meanwhile, the MR findings revealed a detrimental association between alcohol intake frequency, insomnia, hypertension, and early AFB and MO incidence. DISCUSSION:Overall, our study demonstrated various causal risk factors for migraine and its subtypes risk, providing insights into its pathogenesis and potential prevention strategies. Further research is needed to validate these findings and explore their clinical implications and underlying mechanisms.

Long-term infection with Helicobacter pylori (H. pylori) leads to elevated serum gastrin levels, which are closely related to gastric cancer. It is important to reduce serum gastrin levels after H. pylori infection. Dopamine (DA) receptor 1 (D1R) is expressed on G cells in the gastric antrum. Parietal cells produce DA, which inhibits somatostatin (SOM) release through D2R on D cells in the gastric mucosa. Whether targeted intervention in DRs can improve high gastrin levels after H. pylori infection remains to be explored. In this study, human gastric tissue, H. pylori-infected mice, D1R and D2R knockout mice, RT-qPCR, enzyme-linked immunosorbent assay (ELISA), immunohistochemical (IHC), Western blot, and ex vivo incubation of gastric mucosae were used. We found that H. pylori infection destroyed the mitochondria of parietal cells and reduced DA content in the gastric mucosa at 10 wk after infection. Moreover, gastrin-positive cell numbers and serum gastrin levels were increased. D1R, but not D2R, was observed in G cells. DA promoted gastric gastrin secretion. Interestingly, both D1- and D2-like agonists mimicked the effect of DA on the gastrin secretion, which was antagonized by their antagonists. Blocking D2R with domperidone or knocking out D2R resulted in decreased gastrin-positive cell numbers and gastrin levels but increased SOM levels at 10 wk after H. pylori infection. Our findings highlight the key regulatory effect of D2R on gastrin secretion and elucidate the role of domperidone in reducing the elevated gastrin level associated with H. pylori infection.NEW & NOTEWORTHY We report novel findings that blocking D2Rs, not D1Rs, decreased the number of gastric gastrin-positive cells and gastrin levels in H. pylori-infected mice. Gastric gastrin secretion induced by DA was indirectly mediated via D2Rs, which suppressed SOM release. These results provide an experimental basis for local regulation of gastric gastrin secretion by DA through D2Rs, offering a potential strategy for preventing and treating high gastrin levels in H. pylori infection.

Ischemic stroke (IS) is a major cause of disability and death worldwide. However, previous observational studies failed to establish the causality between various exposures and IS occurrence. Currently, an increasing number of Mendelian randomization (MR) studies have been performed to investigate the causal effects of exposure factors on IS risk, but the results remain inconsistent and inconclusive. Thus, our systematic review summarized all published MR studies focusing on IS and its subtypes, and further identified causal relationships with robust evidence. We retrieved PubMed and Embase databases for MR analyses exploring the correlation of genetically determined exposures with the risk of IS and its subtypes. For publications selected in the main analysis, we summed up these MR results and classified the strength of evidence into Grade 1–4 based on the significance and concordance of the findings from the primary and complementary MR methods, as well as the robustness of sensitivity analyses. After conducting a comprehensive search, a total of 207 published studies with 1199 MR associations were included. Among these causal correlations, 8 (Grade 1) and 81 (Grade 2) were graded as robust evidence, while 226 (Grade 3) and 884 (Grade 4) causal relationships were considered to have insufficient reliability. Specifically, with regard to IS susceptibility, genetically predicted diastolic blood pressure, type 2 diabetes, Parkinson’s disease, and primary aldosteronism were evaluated as the prominent robust causal determinants. As for IS subtypes, genetically determined higher vitamin K1 levels and primary aldosteronism were related to greater occurrence of large artery stroke and small vessel stroke, respectively, whereas increased adult height was associated with a lower risk of small vessel stroke but a higher risk of cardioembolic stroke. Our field synopsis systematically summarized and evaluated the evidence strength for causality between various exposures and the occurrence of IS and its subtypes, and ultimately identified 89 causal relationships as convincing findings. We hope that our results can provide constructive and impressive insights for developing effective IS prevention strategies.