Context-dependent TLR4 signaling in cardiovascular disease: linking immunometabolic regulation to cellular remodeling and precision intervention

Toll-like receptor 4 (TLR4) has long been recognized as a canonical innate immune receptor that promotes inflammation in cardiovascular disease. However, this pathway-centered view underestimates the complexity and specificity of TLR4 signaling in the cardiovascular system. Here, we propose a framework in which TLR4 functions as a context-dependent signaling node linking inflammatory, metabolic, and stress-associated cues to distinct cellular state transitions and survival outcomes. Across atherosclerosis, myocardial infarction (MI), heart failure (HF), thrombotic disorders, aortic aneurysm and dissection (AA/AD), hypertension, diabetic cardiomyopathy (DCM), and Kawasaki disease, TLR4-associated signaling results in distinct pathological outcomes according to the cell identity, ligand repertoire, metabolic state, tissue microenvironment, and disease stage. In endothelial cells (ECs), VSMCs, cardiomyocytes, and innate immune cells, these responses range from barrier dysfunction, metabolic inflexibility, and inflammatory activation to multiple forms of regulated cell death, fibrosis, and structural remodeling. Importantly, these processes are biologically distinct, and the strength of the evidence varies substantially among mechanisms, with many proposed cell-specific functions still lacking cell-specific validation in vivo. Genetic and pharmacological loss-of-function studies nevertheless demonstrate that TLR4 modulation can alter disease phenotypes in multiple cardiovascular settings. This framework provides a mechanistic basis for understanding why indiscriminate TLR4 inhibition has limited translational potential and supports a shift toward cell-selective, pathway-biased, and temporally restricted immunomodulation. Therefore, defining when, where, and in which cellular context TLR4 signaling becomes pathogenic may help connect immunometabolic signaling with precision interventions across cardiovascular diseases.