Extremely high and low HDL-C levels, cholesterol dysregulation, and cancer: a call for functional assessment

The role of high-density lipoproteins (HDL) in cardiovascular disease, especially in atherosclerosis, is well known. Lower HDL-cholesterol levels are consistently linked to a higher risk of major atherosclerotic cardiovascular events (MACE), while higher levels have generally been considered protective.1 However, new evidence questions this straightforward relationship. Recent research indicates that very high HDL-cholesterol levels may not confer additional health benefits and could even be harmful. As Shi et al. demonstrated, HDL-cholesterol levels below 30 mg/dL and above 80 mg/dL are both associated with increased all-cause mortality in men and women, suggesting a U-shaped relationship rather than a simple inverse one. These findings have led to a broader reevaluation of HDL as a biomarker and its roles beyond just protecting against atherosclerosis. Growing evidence also links HDL-cholesterol to neurological disease and various cancers, suggesting that HDL is a pluripotent particle with functions extending far beyond lipid transport. HDL’s potential antitumoral properties are often attributed to its antioxidant activity and its cholesterol efflux capacity, both of which may mitigate oxidative DNA damage and thereby reduce oncogenic transformation. At the same time, the complex involvement of cholesterol in solid tumours, where accumulation of intracellular cholesterol supports proliferation, signal transduction, and membrane synthesis, raises important questions about HDL's bidirectional capacity to both remove and deliver cholesterol through mechanisms largely mediated by the scavenger receptor class B type I (SR-BI).2 SR-BI is a major HDL receptor that facilitates selective uptake of cholesteryl esters, and its overexpression has been shown to promote malignant behaviour in lung adenocarcinoma. High SR-BI expression is associated with increased cell proliferation, invasion, metastatic potential, and activation of oncogenic signalling pathways that depend on cholesterol-rich membrane microdomains.2 Therefore, even in the presence of preserved HDL functionality, the tumour acting as the biologically dysregulated component may appropriate cholesterol from this lipoprotein via enhanced uptake mechanisms, thereby facilitating tumour proliferation. Clinically, elevated SR-BI levels correlate with advanced tumour stage, lymph node involvement, and reduced overall survival, suggesting that SR-BI functions not only as a biomarker of aggressive disease but also as a mechanistic driver of lung cancer progression.2