Editorial: Lipids in Immunometabolism

Abstract

acids in modulating macrophage phenotype and function. Fatty acids selectively engage pattern recognition receptors, triggering intracellular signalling cascades that rewire cellular energetics and shape macrophage polarization. Expanding this discussion, Juan P. Rodríguez and colleagues consider additional lipid species, including oxylipins and phospholipids, demonstrating that lipids function not only as structural components but also as signalling mediators that influence macrophage behaviour beyond metabolic regulation alone. Together, these studies reveal a complex interdependence between macrophage polarization and lipid phenotype, underscoring the value of integrating lipidomics into multiomic profiling approaches to uncover novel therapeutic strategies for immune-mediated and inflammation-related disorders, including inflammaging. Collectively, the contributions in this issue highlight how altered lipid metabolism and specific lipid species influence immune dysfunction and disease progression across diverse conditions, including metabolic dysfunction-associated fatty liver disease (MAFLD), obesity-related immune impairment, and chronic endometritis. In a large two-stage Chinese study, Zhao et al showed that in MAFLD, the liver's central role in lipid handling means that lipid accumulation provokes systemic inflammation; composite inflammatory markers linked to dysregulated lipid metabolism predict disease risk beyond traditional metabolic parameters, emphasizing that lipid-associated inflammation is integral to pathogenesis. Wilkin et al demonstrated that in obesity, peripheral invariant NKT (iNKT) cells exhibit activation and dysfunction driven by metabolic stress, reflecting broader lipid-mediated immune perturbations characteristic of obese states. Importantly, Matsuda et al showed that in chronic endometritis, dysregulation of SREBP1-a master regulator of lipid biosynthesis-reduces polyunsaturated fatty acids such as EPA in endometrial phospholipids, perpetuating inflammation and increasing miscarriage risk. Notably, dietary EPA supplementation restores lipid balance and mitigates inflammatory pathology, directly linking lipid composition to immune resolution and reproductive outcomes. Taken together, the articles in this collection firmly establish lipids as active regulators of immune cell fate and systemic homeostasis. While targeting anabolic and catabolic pathways offers promising therapeutic avenues, the widespread expression of metabolic enzymes across tissues demands precision-based strategies to minimize off-target effects. As the field of immunometabolism continues to mature, integrating lipid-focused approaches will be essential for translating mechanistic insight into clinical benefit.