TLR7: A Dual-Regulatory Immunometabolic Checkpoint at the Crossroads of Obesity-Related Hypertension

Obesity-related hypertension represents a major threat to global cardiovascular health, driven fundamentally by chronic low-grade sterile inflammation rather than simple hemodynamic aberrancy. Recently, the endosomal pattern recognition receptor, Toll-like receptor 7 (TLR7), has emerged as a crucial dual-regulatory immunometabolic checkpoint. Synthesizing current molecular and cellular evidence, this review systematically delineates the context-dependent mechanisms of TLR7 in hypernutritional microenvironments. Traditionally sensing viral nucleic acids, TLR7 is ectopically triggered in obesity by endogenous danger-associated molecular patterns (DAMPs), such as cell-free nucleic acids and modified extracellular vesicles. We decrypt how sustained endosomal TLR7 activation promotes adipose tissue inflammation, insulin resistance, and persistent vascular wall injury by inducing endothelial dysfunction, NADPH oxidase-mediated oxidative stress, and maladaptive arterial remodeling. Furthermore, we evaluate the translational traps of systemic TLR7 inhibition, including compromised host antiviral immunity. Finally, we highlight innovative engineering paradigms, such as computer-aided allosteric modulators (e.g., AlphaFold3) and spatiotemporally controlled perivascular nanomedicines, providing a precise therapeutic roadmap for obesity-related cardiovascular crises.