Natural Bioactive Compounds Targeting the ANGPTL3/4/8 Axis in Dyslipidemia and Cardiometabolic Disease: Molecular Mechanisms, Evidence Hierarchy, and Clinical Translation

Dyslipidemia driven by excess triglyceride-rich lipoproteins (TGRLs) remains a major modifiable determinant of atherosclerotic cardiovascular disease (ASCVD). Over the past decade, the angiopoietin-like protein (ANGPTL) family (specifically ANGPTL3, ANGPTL4, and ANGPTL8) has emerged as a central regulatory axis controlling lipoprotein lipase (LPL) activity and the tissue-specific partitioning of circulating triglycerides. Human genetic studies of loss-of-function variants and the clinical success of biologic ANGPTL3 inhibitors have validated this axis as a therapeutic target, but these agents are costly, parenterally administered, and reserved for severe or refractory dyslipidemia. In parallel, a growing body of preclinical work has identified naturally occurring bioactive compounds, including citrus polymethoxyflavones, dietary polyphenols, marine- and plant-derived fatty acids, royal jelly constituents, and polysaccharides, which can modulate ANGPTL3, ANGPTL4, or ANGPTL8 expression and downstream LPL activity. This review synthesizes the molecular mechanisms by which these compounds engage the ANGPTL3/4/8 axis, situates the supporting evidence within a hierarchy that spans hepatocyte and myocyte cell culture, rodent and non-human primate models, and the scarce available human trials, and contrasts this evidence base against the mature clinical data underpinning pharmacological ANGPTL inhibitors such as evinacumab. We identify liver X receptor alpha (LXRα) and hepatocyte nuclear factor 4 alpha (HNF4α) as proposed transcriptional nodes for structurally diverse natural ligands, noting that no compound has been shown to engage either receptor directly, and that a requirement for the transcription factor has been established by loss-of-function experiment only for HNF4α, in a single compound and cell line, and we discuss translational obstacles including limited oral bioavailability, interspecies dosing discrepancies, and the near-total absence of adequately powered human outcome trials. We conclude that natural bioactive compounds represent a mechanistically plausible but clinically immature adjunctive strategy for modulating the ANGPTL3/4/8 axis, and we outline the preclinical and clinical research priorities required to move this field toward evidence-based application in cardiometabolic disease management.