Background: The proteome is a key source of therapeutic targets. We conducted a comprehensive Mendelian randomization analysis across the proteome to identify potential protein markers and therapeutic targets for abdominal aortic aneurysm (AAA). Methods and Results: Our study used plasma proteomics data from the UK Biobank, comprising 2923 proteins from 54 219 individuals, and from deCODE Genetics, which measured 4907 proteins across 35 559 individuals. Significant proteomic quantitative trait loci were used as instruments for Mendelian randomization. Genetic associations with AAA were sourced from the AAAgen consortium, a large‐scale genome‐wide association study meta‐analysis involving 37 214 cases and 1 086 107 controls, and the FinnGen study, which included 3869 cases and 381 977 controls. Sequential analyses of colocalization and summary‐data‐based Mendelian randomization were performed to verify the causal roles of candidate proteins. Additionally, single‐cell expression analysis, protein–protein interaction network analysis, pathway enrichment analysis, and druggability assessments were conducted to identify cell types with enriched expression and prioritize potential therapeutic targets. The proteome‐wide Mendelian randomization analysis identified 34 proteins associated with AAA risk. Among them, 2 proteins, COL6A3 and PRKD2, were highlighted by colocalization analysis, summary‐data‐based Mendelian randomization, and the heterogeneity in an independent instrument test, providing the most convincing evidence. These protein‐coding genes are primarily expressed in macrophages, smooth muscle cells, and mast cells within abdominal aortic aneurysm tissue. Several causal proteins are involved in pathways regulating lipid metabolism, immune responses, and extracellular matrix organization. Nine proteins have already been targeted for drug development in diabetes and other cardiovascular diseases, presenting opportunities for repurposing as AAA therapeutic targets. Conclusions: This study identifies causal proteins for AAA, enhancing our understanding of its molecular cause and advancing the development of therapeutics.

Background: Vascular inflammation triggers endothelial dysfunction, a pivotal factor in the pathogenesis of diabetic vascular complications. Complement component 1q (C1q), a crucial component of the immune system, is implicated in inflammation and immune responses. However, its role in modulating endothelial function in diabetes remains poorly understood. In this study, we aimed to investigate how C1q influences endothelial inflammation in diabetes and the underlying signaling mechanisms involved. Methods: Gene expression in the aortas of streptozotocin‐induced mice or primary endothelial cells was detected using real‐time quantitative polymerase chain reaction, western blot, and immunofluorescence staining. Molecular docking identified dl ‐citrulline as a target for C1qa. Dihydroethidium staining was used to assess vascular reactive oxygen species generation, while Evans blue staining was used to evaluate vascular permeability. Results: Here, we demonstrated that the upregulation of C1q in the aortic endothelial cells significantly reduces the expression of Nr4a1 (orphan nuclear receptor 4a1) and activates the nuclear factor κB signaling pathway, leading to vascular damage. Increasing Nr4a1 expression can mitigate C1q‐induced vascular injury. Additionally, the small molecule dl ‐citrulline downregulates C1q expression and alleviates endothelial inflammation in diabetes. Overexpression of Hoxa3 (homeobox a3), an upstream negative regulator of C1q transcription, protects against diabetic vascular injury. Conclusions: Together, these findings highlight that C1q downregulation ameliorates endothelial inflammation in diabetes, providing mechanistic insights for developing therapeutic strategies against diabetic vascular complications.

Background: Myeloproliferative neoplasms (MPN), a group of chronic hematologic neoplasms, are driven by inflammatory mechanisms that influence disease initiation and progression. Emerging evidence highlights the gut microbiome and plasma metabolome as pivotal immunomodulators, yet their causal roles in MPN pathogenesis remain uncharacterized. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to systematically evaluate causal relationships between 196 gut microbial taxa, 526 plasma metabolites, and MPN risk. Instrumental variables were derived from genome-wide association studies (GWASs) of microbial/metabolite traits. Validation utilized 16S rRNA sequencing data from NCBI Bioproject PRJNA376506. Mediation and multivariable MR analyses elucidated metabolite-mediated pathways linking microbial taxa to MPN. Results: Our MR analysis revealed that 7 intestinal taxa and 17 plasma metabolites are causally linked to MPN. External validation confirmed the three taxa’s differential abundance in MPN cohorts. Mediation analysis revealed two mediated relationships, of which succinylcarnitine mediated 14.5% of the effect, and lysine 27.9%, linking the Eubacterium xylanophilum group to MPN. Multivariate MR analysis showed that both succinylcarnitine (p = 0.004) and lysine (p = 0.040) had a significant causal effect on MPN. Conclusions: This study identifies novel gut microbiota–metabolite axes driving MPN pathogenesis through immunometabolic mechanisms. The validated biomarkers provide potential therapeutic targets for modulating inflammation in myeloproliferative disorders.

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness driven by elevated intraocular pressure from compromised aqueous outflow. While genome-wide association studies have identified numerous risk loci, specific candidate proteins and their cellular mechanisms remain elusive. We employed a multi-omics framework integrating UK Biobank plasma proteomics (N = 53,022) and large-scale POAG GWAS summary statistics. We performed a Proteome-Wide Association Study, Mendelian Randomization, and Bayesian colocalization to infer causality. Identified candidates were mapped to human and mouse ocular scRNA-seq atlases to characterize cell-type specificity, followed by druggability assessments. We prioritized five putative causal proteins, with SEL1L and TFPI demonstrating the strongest evidence. Cross-species scRNA-seq revealed that SEL1L and SERPINF1 are robustly expressed in the trabecular meshwork (TM), particularly the juxtacanalicular tissue, implicating them in outflow resistance. Conversely, TFPI and SLC9A3R2 localize to Schlemm’s canal endothelium, suggesting a role in modulating barrier function. Pathway analyses highlighted endoplasmic reticulum protein processing and coagulation cascades. This study maps putative causal POAG proteins to conventional outflow pathway cells, highlighting SEL1L as a novel target for TM homeostasis and TFPI for drug repurposing, thereby providing data-driven hypotheses to facilitate precision glaucoma therapeutics.

BACKGROUND: Hypertension is a prevalent cardiovascular disorder involving endothelial cell dysfunction. ITLN1 (Intelectin-1) is a fat-derived secreted adipokine that has been shown to enhance endothelium-dependent vasodilation through molecular signaling pathways that remain unclear. METHODS: First, we generated endothelial-specific ITLN1 knockout (ITLN1 _EC ^−/− ) mice to evaluate the functional consequences of ITLN1 deficiency on vascular homeostasis. Subsequently, experiments combining RNA-Seq, qRT-PCR, immunoblotting, immunofluorescence, and nitric oxide quantification were used to elucidate the underlying signaling pathways involved. Finally, virtual molecular docking was used to identify puerarin 6-O-xyloside as a selective ITLN1-binding compound. RESULTS: Hypertensive mice presented reduced ITLN1 abundance and decreased endothelial ITLN1 mRNA levels. Further studies revealed that ITLN1 overexpression via adenoviral vectors improved vascular relaxation in hypertensive models. Mechanistically, ITLN1 restored endothelial nitric oxide synthase phosphorylation by suppressing Wnt5b-JNK (c-jun N-terminal kinase) signaling, thereby increasing nitric oxide production. We subsequently elucidated ITLN1-modulating molecules and found that puerarin 6-O-xyloside upregulated ITLN1 expression and augmented vasodilation. Finally, ZNF460 was identified as a transcriptional repressor of ITLN1 in endothelial cells. CONCLUSIONS: This study identified ITLN1 as a potential therapeutic target for hypertension. Upregulating ITLN1 protected against endothelial dysfunction by modulating Wnt5b-JNK/endothelial nitric oxide synthase signaling, with puerarin 6-O-xyloside serving as a promising ITLN1 activator.