An NRIP1-Centric Monocyte Immunogenetic Bridge Between Heart Failure and Ischemic Stroke.

Background: Heart failure (HF) and ischemic stroke (IS) frequently co-occur and worsen each other. Circulating immune cells may act as a cross-organ inflammatory bridge, but the key immune lineage, genetically supported mediators, and druggable targets remain unclear. Objective: To identify the immune-cell lineage, candidate gene, and tractable intervention target linking HF and IS. Methods: Bidirectional Mendelian randomization (MR) of genome-wide association study summary statistics was used to assess causal links between HF and IS. Mouse single-cell transcriptomic datasets from HF and IS models were integrated to define a shared immune/stromal atlas and characterize Ly6C⁺ monocyte expansion. Ly6C⁺ monocyte marker genes were mapped to human orthologs and evaluated using peripheral-blood expression quantitative trait locus data for gene-level MR, followed by expression validation, colocalization, summary-data-based MR, and spatial transcriptomics. In HF single-cell data, Ly6C⁺ monocytes were stratified by Nrip1 expression for cell-cell communication, pathway enrichment, and pseudotime analyses. Candidate-drug prediction, druggability evaluation, molecular docking, molecular dynamics simulation, and in vitro validation were then performed. Results: MR supported a bidirectional positive association between HF and IS. Both diseases showed expansion of inflammatory Ly6C⁺ monocytes at single-cell resolution. Among MR-implicated genes, NRIP1 was prioritized as a key gene associated with reduced IS risk, and genetic and spatial evidence supported its monocyte-mediated role in HF-IS coupling. Nrip1-stratified and pseudotime analyses suggested a homeostatic role through modulation of inflammatory thresholds and communication patterns. Drug prediction and in silico analyses indicated that retinoic acid-related small molecules may bind NRIP1 and exhibit preliminary druggability. In vitro, tretinoin alleviated ischemia-like HMC3 cell injury and inflammation by modulating monocyte NRIP1. Conclusion: An NRIP1-centered monocyte network may represent a tractable immune bridge in HF-IS comorbidity, and tretinoin provides an entry point for NRIP1-targeted intervention.