Lipid metabolism disorder serve as a critical starting point for the development of chronic non-communicable diseases (NCDs). Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) are known for their lipid-lowering properties, but few studies have revealed their differences from the perspective of skeletal muscle endocrinology. Myogenic IL-6 has garnered significant attention for its role in energy distribution. The primary aim of this study was to investigate the effects and mechanisms of EPA and DHA on myogenic IL-6 and lipid metabolism disorders in mice, and to clarify the association between the alleviation of lipid metabolism disorders and myogenic IL-6 mediated by EPA/DHA. We found that EPA and DHA not only prevented high-fat diet-induced lipid metabolism disorders, but also up-regulated the expression of myogenic IL-6 by activating TRPV1/Ca