Roles of Diverse Lipokines in Metabolic Homeostasis and Their Associations With Various Diseases

ABSTRACT Lipokines are a class of lipid‐derived signaling molecules, playing essential roles in regulating metabolic homeostasis and systemic metabolism. In this review, we first comprehensively describe six major lipokines, including palmitoleic acid (C16:1n7), 12,13‐dihydroxy‐9Z‐octadecenoic acid (12,13‐diHOME), fatty acid esters of hydroxy fatty acids (FAHFAs), 12‐hydroxyeicosapentaenoic acid (12‐HEPE), lysophosphatidic acid (LPA), and 15‐hydroxyeicosatetraenoic acid (15‐HETE), focusing on their mechanistic roles in energy metabolism and inflammatory modulation as well as their cross‐talk within different signaling pathways. These lipokines collectively contribute to metabolic homeostasis by regulating multiple pathways, including insulin signaling, AMPK activation, inflammatory modulation, and G‐protein‐coupled receptor‐mediated pathways. Furthermore, we clarify the associations between lipokines and various diseases such as obesity, type 2 diabetes, cardiovascular diseases, non‐alcoholic fatty liver disease, inflammatory disorders, and cancer, and discuss their potential as biomarkers and therapeutic targets. Despite current challenges, including functional complexity, limitations of model systems, and difficulties in clinical translation, lipokines demonstrate promising prospects in the prevention and treatment of metabolic diseases and application in precision medicine. Future research should prioritize the elucidation of the specific action mechanisms of different lipokines, development of highly sensitive detection methodologies, and large‐scale clinical trials to facilitate the translation of the research results into practical medical applications.