Biology of HDL: From Structural Heterogeneity to Dysfunctional Remodeling in Cardiovascular Disease and Comorbidities

The pathogenesis of cardiovascular diseases (CVDs) is intimately linked to cholesterol dysregulation. While high-density lipoprotein cholesterol (HDL-C) is classically considered cardioprotective, contemporary epidemiological evidence reveals a noncausal, often U-shaped, relationship with CVD risk. Static measurements of HDL-C obscure the structural and functional heterogeneity of circulating HDL particles. Under pathological stress, HDL undergoes extensive structural remodeling into dysfunctional HDL, thereby losing its vasculoprotective properties and instead mediating proatherogenic and proinflammatory responses. This review critically evaluates the biogenesis, maturation, and metabolic trajectory of HDL. By integrating recent advancements in proteomics and lipidomics, we map the intricate compositional shifts within HDL subpopulations and clarify the regulatory roles of HDL-associated microRNAs in intercellular communication. We investigate the specific drivers of HDL dysfunction, which is often exacerbated by comorbidities such as diabetes and chronic kidney disease. Furthermore, we outline the methodological transition from automated homogeneous HDL-C quantification to multidimensional profiling. Shifting the clinical focus from HDL quantity to functional quality resolves the HDL-C paradox, helping to drive the development of precision lipidology and targeted therapies to reverse HDL dysfunction in CVDs.