Non-coding RNA-driven cardiovascular immunometabolic reprogramming: from inflammatory endotypes to therapeutic opportunities.

Cardiovascular disease is increasingly recognized as a heterogeneous immunometabolic disorder shaped by inflammation, metabolic rewiring, endothelial dysfunction, mitochondrial stress, and tissue remodeling across diverse cell types. This review provides a hypothesis-generating conceptual synthesis of non-coding RNA-driven cardiovascular immunometabolic reprogramming from an inflammatory endotype-oriented perspective. Because ncRNA profiling has not yet prospectively assigned cardiovascular patient cohorts to validated inflammatory endotypes, we frame mechanism-based endotypes as complementary research constructs rather than clinically deployable diagnostic categories. We discuss how conventional disease labels, including atherosclerosis, myocardial infarction, heart failure, hypertension, and cardiomyopathy, may be cross-mapped to dominant mechanisms such as athero-inflammation, sterile ischemic injury, fibro-inflammatory remodeling, metabolic inflammation, and vascular immune-endothelial dysfunction. We summarize how microRNAs, long non-coding RNAs, circular RNAs, and extracellular vesicle-associated RNA species regulate macrophage cholesterol handling, inflammasome activation, endothelial activation, vascular smooth muscle cell plasticity, cardiomyocyte mitochondrial dysfunction, fibroblast activation, extracellular matrix remodeling, and intercellular communication, with added attention to circRNA tissue-source patterns in cardiac, immune-cell, endothelial, and vascular compartments. We also highlight their context-dependent and cell type-specific actions, which challenge simple protective-versus-pathogenic classifications. Finally, we discuss translational opportunities, including circulating and extracellular vesicle-associated non-coding RNAs as liquid biopsy candidates, RNA-based therapeutics, endotype-enriched study designs, and traditional medicine-inspired multicomponent strategies. Despite barriers related to delivery, specificity, disease stage, species conservation, analytical standardization, and validation, integrated phenotyping, multi-omics profiling, functional perturbation, and biomarker-enriched trials may advance non-coding RNAs as candidate classifiers, regulators, markers, and therapeutic targets in precision cardiovascular medicine.