The treatment of prostate cancer (PCa) continues to pose substantial clinical challenges. The use of large language models (LLMs) to identify the key molecular determinants of PCa progression, followed by experimental biological validation, helps uncover novel therapeutic targets. We developed hierarchical knowledge-guided LLM for risk gene identification (HKLLM-RG), a PCa risk gene identification method. Among the candidate genes identified, ALKBH5 emerged as particularly noteworthy in the analysis. Reduced expression of ALKBH5 correlated with aggressive clinical features and significantly reduced survival in PCa. ALKBH5 inhibits PCa progression and promotes ferroptosis. CHRM3, which is the downstream molecule of ALKBH5, could promote PCa cell proliferation and migration. ALKBH5 regulates CHRM3 in an m6A-dependent manner. Mechanistically, the ALKBH5/CHRM3 axis suppresses AKT signaling, thereby inducing the upregulation of the transcriptional repressor ZNF281. This regulatory cascade subsequently downregulates the expression of SLC3A2 and GPX4, ultimately sensitizing cells to ferroptosis. Thus, AZD5363 and RSL3 targeting the ALKBH5/CHRM3/ZNF281 axis can effectively synergize to treat PCa by promoting ferroptosis. Taken together, this study leverages LLM-guided discovery to delineate a novel ALKBH5/CHRM3/ZNF281 regulatory axis controlling ferroptotic susceptibility in PCa. Importantly, a synergistic therapeutic strategy was identified by combining RSL3 with AZD5363, providing novel therapeutic targets and directions for PCa treatment.

Although immunotherapy has transformed the treatment of several genitourinary malignancies, its role in prostate cancer remains limited. Combining immunotherapy with targeted therapies has emerged as a promising approach to enhance immune responses in prostate cancer. We aimed to systematically evaluate the efficacy and safety of immunotherapy combined with targeted therapy in the treatment of prostate cancer. We conducted a detailed literature search across Embase, Scopus, PubMed, Web of Science, and the Cochrane Library to include clinical trials enrolling adults with histologically confirmed prostate cancer treated with a combination of targeted therapy and immunotherapy. A systematic review and meta-analysis were performed according to a registered protocol. A total of 21 studies from 19 clinical trials, encompassing 5702 participants, were included. The studies evaluated 12 unique therapeutic combinations involving six targeted agents and four immunotherapies. Seven trials compared combination therapy with monotherapy. Pooled analyses showed that combination therapy significantly improved disease control rate (RR = 1.42), complete response (RR = 2.56), and partial response (RR = 2.13), albeit with a higher incidence of adverse events. In single-arm studies, the pooled median progression-free survival was 5.14 months, and median overall survival was 16.79 months. The androgen receptor signaling inhibitor subgroup exhibited longer survival than the PARP inhibitor subgroup. Combination immunotherapy and targeted therapy demonstrate superior efficacy over monotherapy in prostate cancer but increase the risk of toxicity. These promising results warrant further validation in large-scale, well-designed randomized trials.

Importance:Antibody-drug conjugates (ADCs), including enfortumab vedotin, disitamab vedotin, and sacituzumab govitecan, are altering the therapeutic landscape for locally advanced or metastatic urothelial carcinoma (la/mUC). Comprehensive comparative evidence evaluating their translation in the clinical setting and modifying clinical covariates is required. Objective:To synthesize multidimensional evidence from interventional and observational settings to evaluate clinical outcomes, define the evolving therapeutic positioning of enfortumab vedotin, disitamab vedotin, and sacituzumab govitecan, and identify drivers of heterogeneity through meta-regression. Data Sources:PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar were searched from database inception to October 23, 2025. Study Selection:Interventional and observational studies of adults with la/mUC treated with enfortumab vedotin, disitamab vedotin, or sacituzumab govitecan. Data Extraction and Synthesis:Independent reviewers extracted data following PRISMA guidelines. A rigorous metadata deduplication algorithm prevented patient double-counting. Random-effects models pooled data. Bayesian network meta-analysis (NMA) used reconstructed individual patient data. Inverse-variance weighted meta-regression assessed clinical covariates. Main Outcomes and Measures:Primary outcomes were disease control rate, objective response rate (ORR), and clinical complete response. Results:Forty independent studies involving 6085 patients were included. For enfortumab vedotin monotherapy, the pooled ORR was 43.9% (95% CI, 40.4%-47.5%) in interventional studies and 44.6% (95% CI, 41.0%-48.2%) in observational cohorts. For enfortumab vedotin plus pembrolizumab, interventional cohorts were associated with a pooled ORR of 67.5% (95% CI, 63.5%-71.3%) overall and 65.4% (95% CI, 60.0%-70.5%) in cisplatin-ineligible patients. Furthermore, disitamab vedotin plus programmed cell death protein 1 (PD-1) inhibitors was associated with an ORR of 74.7% (95% CI, 69.4%-79.4%) in interventional trials and 61.7% (95% CI, 52.6%-70.1%) observationally. Meta-regression identified prior PD-1/L1 exposure (β = -0.071; P = .003) and treatment regimen (β = -0.890; P < .001) as factors associated with primary response. Notably, the pure randomized clinical trial network meta-analysis of first-line treatments for cisplatin-ineligible patients revealed that enfortumab vedotin monotherapy was associated with a statistically significant overall survival advantage over chemotherapy (HR, 0.50; 95% CI, 0.29-0.86; posterior probability >99%). Conclusions and Relevance:In this meta-analysis of ADCs for la/mUC, enfortumab vedotin-based regimens were associated with robust outcomes across clinical settings, and disitamab vedotin combined with immunotherapy was associated with potent clinical activity. Meta-regression indicated that prior immunotherapy exposure and hepatic tumor burden were associated with attenuated treatment responses.

Importance Antibody-drug conjugates (ADCs), including enfortumab vedotin, disitamab vedotin, and sacituzumab govitecan, are altering the therapeutic landscape for locally advanced or metastatic urothelial carcinoma (la/mUC). Comprehensive comparative evidence evaluating their translation in the clinical setting and modifying clinical covariates is required. Objective To synthesize multidimensional evidence from interventional and observational settings to evaluate clinical outcomes, define the evolving therapeutic positioning of enfortumab vedotin, disitamab vedotin, and sacituzumab govitecan, and identify drivers of heterogeneity through meta-regression. Data Sources PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar were searched from database inception to October 23, 2025. Study Selection Interventional and observational studies of adults with la/mUC treated with enfortumab vedotin, disitamab vedotin, or sacituzumab govitecan. Data Extraction and Synthesis Independent reviewers extracted data following PRISMA guidelines. A rigorous metadata deduplication algorithm prevented patient double-counting. Random-effects models pooled data. Bayesian network meta-analysis (NMA) used reconstructed individual patient data. Inverse-variance weighted meta-regression assessed clinical covariates. Main Outcomes and Measures Primary outcomes were disease control rate, objective response rate (ORR), and clinical complete response. Results Forty independent studies involving 6085 patients were included. For enfortumab vedotin monotherapy, the pooled ORR was 43.9% (95% CI, 40.4%-47.5%) in interventional studies and 44.6% (95% CI, 41.0%-48.2%) in observational cohorts. For enfortumab vedotin plus pembrolizumab, interventional cohorts were associated with a pooled ORR of 67.5% (95% CI, 63.5%-71.3%) overall and 65.4% (95% CI, 60.0%-70.5%) in cisplatin-ineligible patients. Furthermore, disitamab vedotin plus programmed cell death protein 1 (PD-1) inhibitors was associated with an ORR of 74.7% (95% CI, 69.4%-79.4%) in interventional trials and 61.7% (95% CI, 52.6%-70.1%) observationally. Meta-regression identified prior PD-1/L1 exposure (β = −0.071; P = .003) and treatment regimen (β = −0.890; P < .001) as factors associated with primary response. Notably, the pure randomized clinical trial network meta-analysis of first-line treatments for cisplatin-ineligible patients revealed that enfortumab vedotin monotherapy was associated with a statistically significant overall survival advantage over chemotherapy (HR, 0.50; 95% CI, 0.29-0.86; posterior probability >99%). Conclusions and Relevance In this meta-analysis of ADCs for la/mUC, enfortumab vedotin-based regimens were associated with robust outcomes across clinical settings, and disitamab vedotin combined with immunotherapy was associated with potent clinical activity. Meta-regression indicated that prior immunotherapy exposure and hepatic tumor burden were associated with attenuated treatment responses.

S. Table 1: List of PEACE Consortium members. S. Table 2: Sample database used for the study for Panel, Exome and RNASeq samples. S. Table 3: Overview of lines of treatment given to each patient. S. Table 4: Lesions and patients included in the lesion-level response to ICI analysis. S. Table 5: Hallmark genesets significantly upregulated in normal tissue vs tumor tissue. Table shows p-values for tissue type, purity; T value for tissue type, purity; q-value for tissue type, purity (FDR corrected). S. Table 6: Hallmark genesets significantly upregulated in tumor tissue vs normal tissue. Table shows p-values for tissue type, purity; T value for tissue type, purity; q-value for tissue type, purity (FDR corrected). S. Table 7: Genes included in the target panel. S. Table 8: Tree topology comparisons between manually constructed trees and pairtree-constructed trees.

ABSTRACT:Prostate cancer (PCa) presents a significant global health challenge, and cachexia in end-stage PCa further reduces survival time and deteriorates patient quality of life. This necessitates nuanced approaches to prevention, diagnosis, and treatment. This review analyzes the complex role of growth differentiation factor 15 (GDF15) in various aspects of PCa, including metabolism, chemoresistance, metastasis, and clinical implications. Mechanically, the interactions of GDF15 with PCa lipid metabolism and stromal activation are hypothesized to drive PCa progression and promote cachexia. GDF15's role in PCa bone metastasis is mediated through interactions with osteoblasts and osteoclasts. Furthermore, GDF15's role in chemoresistance emphasizes its impact on drug responses and suggests a potential therapeutic target. Clinically, GDF15 has shown potential as a biomarker, offering diagnostic precision and prognostic value, particularly when combined with established markers such as prostate-specific antigen. The review concludes with a discussion on several monoclonal antibodies targeting GDF15 in clinical trials, such as AV-380, NGM120, Visugromab, and AZD8853, highlighting promising strategies for novel therapies and precision medicine.

The treatment of prostate cancer (PCa) remains challenging, and while melatonin (MEL) has demonstrated therapeutic potential, its precise mechanisms require further elucidation. Through integrated in vitro, in vivo, and bioinformatics analyses, this study demonstrated that MEL functioned as a novel ferroptosis inducer in PCa by disrupting androgen receptor (AR) liquid-liquid phase separation (LLPS). We found that MEL effectively inhibited PCa proliferation, migration, and invasion in vitro while suppressing tumor growth safely in mice models. Mechanistically, MEL impaired AR LLPS dynamics, reducing AR-driven transcription of minichromosome maintenance protein 5 (MCM5). MCM5 was a clinically relevant biomarker associated with aggressive PCa and poor survival. Crucially, downregulated MCM5 attenuated its physical interaction with NRF2, leading to uncontrolled activation of the NRF2/HMOX1 pathway, GPX4 suppression, and accumulation of ferroptosis hallmarks. These findings defined an AR/MCM5/NRF2 axis regulating ferroptosis susceptibility, establishing MEL as the first-reported ferroptosis inducer that expands the mechanistic foundation and therapeutic potential of MEL-based PCa treatment strategies.

OBJECTIVE:The study aims to conduct a diagnostic test accuracy systematic review and meta-analysis to compare the abbreviated biparametric magnetic resonance imaging (MRI) [bpMRI; T2-weighted imaging (T2WI) and DWI] and multiparametric MRI [mpMRI; T2WI, DWI and dynamic contrast-enhanced (DCE) MRI] for the detection of clinically significant prostate cancer (csPCa) in treatment-naïve patients. METHODS AND MATERIALS:Two independent reviewers performed a systematic search of electronic databases (PubMed, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov) from January 2012 to July 2025 using predefined search criteria. The index test was bpMRI and/or mpMRI, and the reference standard was histopathological findings from prostate biopsy or radical prostatectomy. The Quality Assessment of Diagnostic Accuracy Studies tool was used to assess the risk of bias of included articles. Assessing the methodological quality of systematic reviews, and Grading of Recommendations, Assessment, Development and Evaluation working group classification were employed to assess the study quality. The sensitivity and specificity were pooled by a bivariate random-effects model and graphically presented with summary receiver operator curve (SROC) curves. Multiple subgroup analyses of possible covariates were employed to explore potential heterogeneity. RESULTS:A total of 25 studies were included in our review. For bpMRI, the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) was 0.87 (95% CI, 0.83-0.92), 0.67 (95% CI, 0.59-0.76), 2.7 (95% CI, 2.1-3.4), 0.19 (95% CI, 0.14-0.24), and 14 (95% CI, 10-21), respectively. For mpMRI, the pooled sensitivity, specificity, PLR, NLR, and DOR was 0.89 (95% CI, 0.86-0.93), 0.66 (95% CI, 0.57-0.75), 2.6 (95% CI, 2.1-3.3), 0.16 (95% CI, 0.11-0.22), 17 (95% CI, 11-25). The area under the curve value of SROC curve was 0.88 (95% CI, 0.83-0.89), 0.87 (95% CI, 0.84-0.89) for bpMRI and mpMRI. Meta-regression showed that mpMRI achieved significantly higher sensitivity than bpMRI, while the two modalities demonstrated comparable specificity. CONCLUSIONS:This systematic review and meta-analysis suggested that mpMRI offered significantly higher sensitivity while maintaining equivalent specificity for csPCa detection compared to bpMRI. Whether adopting bpMRI as a substitute for mpMRI remains an issue and warrants careful consideration. More prospective multicenter, comparative studies are warranted to validate our results.

Background: Glucose metabolism in breast cancer has a potential effect on tumor progression and is related to the immune microenvironment. Thus, this study aimed to develop a glucose metabolism-tumor microenvironment score to provide new perspectives on breast cancer treatment. Method: Data were acquired from the Gene Expression Omnibus and UCSC Xena databases, and glucosemetabolism-related genes were acquired from the Gene Set Enrichment Analysis database. Genes with significant prognostic value were identified, and immune infiltration analysis was conducted, and a prognostic model was constructed based on the results of these analyses. The results were validated by in vitro experiments with MCF-7 and MCF-10A cell lines, including expression validation, functional experiments, and bulk sequencing. Single-cell analysis was also conducted to explore the role of specific cell clusters in breast cancer, and Bayes deconvolution was used to further investigate the associations between cell clusters and tumor phenotypes of breast cancer. Results: Four significant prognostic genes (PMAIP1, PGK1, SIRT7, and SORBS1) were identified, and, through immune infiltration analysis, a combined prognostic model based on glucose metabolism and immune infiltration was established. The model was used to classify clinical subtypes of breast cancer, and PMAIP1 was identified as a potential critical gene related to glucose metabolism in breast cancer. Single-cell analysis and Bayes deconvolution jointly confirmed the protective role of the PMAIP1+ luminal cell cluster.

Despite therapeutic advances, prostate cancer remains lethal for most patients. Accelerated development of novel therapies requires validated surrogate endpoints to circumvent prolonged survival follow-up in phase III trials. This review systematically evaluates intermediate clinical endpoints (ICEs) in prostate cancer to establish methodologically robust alternatives to overall survival (OS). We first synthesized methodological standards for ICE validation. Subsequent analysis encompassed phase III trials (PubMed/Web of Science, Jan. 2025) in metastatic castration-sensitive (mCSPC) and -resistant prostate cancer (mCRPC), requiring: randomization, therapeutic intervention, OS as primary/co-primary endpoint, ≥1 ICE (radiographic progression-free survival (rPFS), milestone survival), and ≥70 participants. Surrogacy was quantified via two-stage meta-analysis, with R2 ≥ 0.7 defining validity. Metastasis-free survival (MFS) is validated for localized disease, enabling trial endpoint substitution. In advanced stages, evidence for ICEs remains critically deficient. Our analysis identifies milestone survival as a promising ICE candidate in mCSPC and mCRPC, demonstrating strong trial-level correlation with OS. Current ICE validation in prostate cancer is disproportionately focused on localized disease, leaving advanced-stage therapeutic development constrained. While milestone survival shows surrogacy potential, endpoint validation remains methodologically challenging even in rigorously designed trials. This work underscores the imperative to accelerate ICE standardization through unified methodological frameworks and collaborative cross-trial analyses.

Background and aims To evaluate the prognostic significance of preoperative creatine kinase (CK) levels in bladder cancer (BCa) patients who underwent radical cystectomy (RC). Materials and methods 570 BCa patients with RC were identified between 2010 and 2020. 108.5 U/L of CK levels were defined as the cutoff value. Logistic regression analysis and Cox regression models were performed to evaluate the association between CK levels and oncologic outcomes. Subgroup analyses were performed to address cofounding factors. Results Preoperative low CK levels were associated with worse recurrence-free survival (RFS, log-rank P = 0.001) and overall survival (OS, log-rank P = 0.002). Multivariate analysis revealed that preoperative low CK levels were an independent predictor for worse RFS (hazard ratio [HR]: 1.683; P < 0.001) and OS (HR: 1.567; P = 0.002). Conclusions The preoperative low CK level independently predicts worse survival outcomes in BCa after RC. Incorporating it into prediction models might be valuable to assist risk stratification.

Introduction: Previous studies showed exercise have efficacies for androgen deprivation therapy (ADT) adverse effects. To compare the efficacies of different exercises on ADT adverse effects, we conducted the network meta-analysis (NMA). Methods: Literature retrieval was performed in PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). Nineteen studies (1,184 participants) were included. All analyses were performed in R 4.1.2 or RevMan 5.4.1. Results: NMA results showed that compared with the control group, both aerobic + resistance training (ART) (MD = 5.92, 95% CI: 0.38; 11.46) and resistance exercise (RE) (MD = 5.62, 95% CI: 2.70; 8.55) improved quality of life (QoL). ART (P score: 0.72) may have superiority over RE (P score: 0.7). ART (MD = -10.89, 95% CI: -17.67; -4.11) significantly improved the performance of 400-m test. RE could significantly improve leg strength (MD = 118, 95% CI: 78.75; 157.25) and chest strength (MD = 13.30, 95% CI: 4.07; 22.53). RE ranked first for strength improvements of leg and chest. Conclusion: ART showed better efficacy for the QoL and significantly improved the performance of 400-m test. RE might be superior for the strengths of leg and chest. ART may be appropriate for patients with less significant muscle strength decline but also other adverse effects of ADT, such as decreased cardiopulmonary function.

The presence of tertiary lymphoid structures (TLSs) associated with distinct treatment efficacy and clinical prognosis has been identified in various cancer types. However, the mechanistic roles and clinical implications of TLSs in genitourinary (GU) cancers remain incompletely explored. Despite their potential role as predictive markers described in numerous studies, it is essential to comprehensively evaluate the characteristics of TLSs, including drivers of formation, structural foundation, cellular compositions, maturation stages, molecular features, and specific functionality to maximize their positive impacts on tumor-specific immunity. The unique contributions of these structures to cancer progression and biology have fueled interest in these structures as mediators of antitumor immunity. Emerging data are trying to explore the effects of therapeutic interventions targeting TLSs. Therefore, a better understanding of the molecular and phenotypic heterogeneity of TLSs may facilitate the development of TLSs-targeting therapeutic strategies to obtain optimal clinical benefits for GU cancers in the setting of immunotherapy. In this review, the authors focus on the phenotypic and functional heterogeneity of TLSs in cancer progression, current therapeutic interventions targeting TLSs and the clinical implications and therapeutic potential of TLSs in GU cancers.

Treatment with androgen-ablative therapies effectively inhibited androgen receptor (AR)-positive (AR+) prostate cancer (PCa) cell subtypes, but it resulted in an increase in AR-negative (AR-) PCa cell subtypes. The present study aimed to investigate the debated mechanisms responsible for the changing proportion of cell types, identifying CXCL8 as a synthetic essential effector of AR- PCa cells. AR- PCa cells were found to be susceptible to CXCL8 depletion or inhibition, which impaired their survival. Mechanistically, androgen-ablative therapies resulted in the suppression of AR signaling, leading to the upregulation of CXCL8 gene transcription. CXCL8, in turn, activated the mTORC1 pathway, which increased de novo cholesterol synthesis by activating sterol regulatory element-binding protein-2 (SREBP2). Together, these results suggested that the CXCL8-mTORC1-SREBP2 axis contributed to the exacerbation of tumorigenicity in AR- PCa cells under androgen-ablative therapies.

Copy number and count data for tumor suppressor genes and oncogenes in primary tumors, PDXs, and PDX-derived cell lines

Context: Data on racial disparities among patients with metastatic castration-resistant prostate cancer (mCRPC) are limited and there is no uniform conclusion on differences by race in this setting. Objective: To provide the latest evidence on racial disparities in survival outcomes between Black and White patients receiving systemic therapies for mCRPC. Evidence acquisition: Our study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We systematically searched the PubMed, Web of Science, and Cochrane Library databases up to September 2023 to identify potentially relevant studies. Overall survival (OS) and progression-free survival (PFS) were the outcomes of interest. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were evaluated. Evidence synthesis: Nine studies involving 9462 patients with mCRPC (2058 Black and 7404 White men) met the eligibility criteria and were included. Pooled estimates demonstrated significantly better OS for Black than for White men (HR 0.75, 95% CI 0.70-0.80; p < 0.0001). The results were similar in a subgroup of men receiving androgen receptor-targeted therapies (HR 0.72, 95% CI 0.66-0.78; p < 0.0001) and a subgroup of men receiving other treatments (HR 0.79, 95% CI 0.71-0.88; p < 0.0001). Likewise, significantly favorable PFS was observed for Black men receiving ARTs in comparison to their White counterparts (HR 0.84, 95% CI 0.71-0.99; p = 0.0373). Conclusions: Overall, our meta-analysis of survival outcomes for men with mCRPC stratified by race revealed a significant survival benefit for Black men in comparison to their White counterparts, regardless of systemic therapeutic agent.

Supplementary figures and tables

ObjectiveTo summarize and indirectly compare the efficacy and safety of different second-line systematic therapies after first-line androgen-receptor targeting therapies (ARTs) for biomarker-unselected metastatic castration-resistant prostate cancer (mCRPC) patients.MethodsStudies published in English up to May 2023 were identified in PubMed, Web of Science and ASCO-GU 2023. Studies accessing the efficacy and safety of second-line systematic therapies after first-line ARTs for biomarker-unselected mCRPC patients were eligible for current systematic review and network meta-analysis (NMA).ResultsThirty-two studies with 5388 patients and 10 unique treatment modalities met our inclusion criteria. Current evidence suggested that docetaxel (DOC) combined with the same ART as first-line (ART1) (ART1 + DOC) were associated with significantly improved PSA response, PSA progression-free survival (PFS) and clinical or radiographic PFS (rPFS) compared with other reported second-line systematic therapies, including DOC. An increase in toxicity was observed with ART1 + DOC. Our NMA indicated that DOC monotherapy was only inferior to ART1 + DOC in improvement disease outcomes. The incidence of toxicity between patients received second-line DOC and an alternative ART (ART2) was similar.ConclusionThe available evidence reviewed in our work suggested a clinical benefit of DOC nomotherapy and DOC plus ART1 as the second-line systematic therapy for biomarker-unselected mCRPC patients progressed on a first-line ART. More studies and RCTs are needed to evaluate the optimal second-line treatments for mCRPC patients with one prior first-line ART.

BackgroundThe benefits of vitamin E (VE) for multiple health outcomes have been well evaluated in many recent studies.ObjectiveThe purpose of this umbrella review was to conduct a systematic evaluation of the possible associations between VE intake and various health outcomes.MethodsWe systematically searched various databases, such as PubMed, Embase, and the Web of Science, to identify related meta-analyses of observational studies and randomized trials. We estimated the effect size of each association by using the random or fixed effects models and the 95% confidence intervals. We used standard approaches to evaluate the quality of the articles (AMSTAR) and classified the evidence into different levels of quality (GRADE).ResultsA total of 1,974 review articles were searched, and 27 articles with 28 health outcomes were yielded according to our exclusion criteria. The intake of VE was inversely associated with the risk of breast cancer, lung cancer, esophageal cancer, gastric cancer, pancreatic cancer, kidney cancer, bladder cancer, cervical neoplasms, cardiovascular disease, Parkinson's disease, depression, age-related cataracts, metabolic syndrome, and fracture. Overall, most of the quality of the evidence was low or very low. Three outcomes (stroke, age-related cataracts, obesity) were identified as having a “moderate” level of quality. The AMSTAR scores for all health outcomes ranged from 5 to 10.ConclusionOur study revealed that VE intake is beneficially related to multiple health outcomes. However, future studies on recommended doses and recommended populations of VE are also needed.Systematic review registrationhttp://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42022339571.