Omega-3 fatty acids in aromatase inhibitor-associated dyslipidemia: mechanisms, clinical evidence, and future perspectives

Aromatase inhibitors (AIs), including anastrozole, letrozole, and exemestane, are widely used as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer. However, prolonged estrogen deprivation induced by AI therapy may adversely affect lipid homeostasis and has been associated with alterations in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C), potentially contributing to long-term cardiovascular risk. The mechanisms underlying these abnormalities appear to involve estrogen-dependent regulation of hepatic lipoprotein metabolism, together with endothelial dysfunction, oxidative stress, and chronic inflammation. Omega-3 polyunsaturated fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have established effects on lipid metabolism and cardiovascular health. Their metabolic actions include activation of peroxisome proliferator-activated receptor-α (PPAR-α), suppression of sterol regulatory element-binding protein-1c (SREBP-1c), modulation of hepatic very-low-density lipoprotein (VLDL) production, enhancement of fatty acid oxidation, and regulation of lipoprotein clearance. However, the effects of EPA and DHA on LDL-C, TC, and HDL-C are less consistent than their triglyceride-lowering effects and may differ according to formulation and dose. In this review, we critically examine the biological mechanisms underlying AI-associated dyslipidemia, compare the lipid effects of individual AIs with tamoxifen, and evaluate the potential mechanisms through which EPA and DHA may modulate cholesterol and lipoprotein metabolism. We further summarize clinical evidence from general dyslipidemia and breast cancer populations and assess its applicability to patients receiving AI therapy. Current evidence supports a strong biological rationale for omega-3 fatty acid supplementation but remains insufficient to establish its efficacy specifically for AI-associated dyslipidemia. Future randomized controlled trials should directly evaluate lipid and cardiovascular outcomes, compare EPA- and DHA-containing formulations, account for differences among individual AIs, and identify patient subgroups most likely to benefit from omega-3-based interventions.