Cutting-edge review on phospholipid metabolism: A new perspective on inflammation regulation in innate immunity

Lipid metabolism plays a pivotal role in immune and inflammatory responses. Phospholipids (PLs), the fundamental components of biological membranes, not only maintain cellular structure and function but also profoundly influence the fate and activity of innate immune cells through metabolic reprogramming.

In the recently published review, Professor Juan Liu from Naval Medical University, Professor Luke O’Neill from Trinity College Dublin, and Dr. Yali Chen from Tongji University discuss the functions and mechanisms of phospholipids in regulating inflammation, as well as their therapeutic potential in treating inflammatory diseases. Their review was published online in the journal Immunity & Inflammation on September 29, 2025.

“This review centers on three aspects,” the authors pointed out “the central role of phospholipid metabolism in innate immunity and inflammation, dysregulated phospholipid metabolism in disease pathogenesis, and the therapeutic potential and future directions.”

Phospholipids, as major components of biological membranes, regulate membrane fluidity and cellular signaling, playing crucial roles in innate immunity and inflammation. Dynamic remodeling of phospholipid metabolism influences immune cell migration, differentiation, and survival, while its metabolites exert diverse regulatory effects on the initiation, amplification, and resolution of inflammation. The review also summarizes the process of phospholipid hydrolysis, mediated by enzymes such as PLA2, PLC, and PLD.

“These enzymes are expressed in various innate immune cells, and could mediate the generation of bioactive lysophospholipids and fatty acids that shape the functional diversity of macrophages, dendritic cells, neutrophils, and mast cells”, the authors mentioned.

Aberrant phospholipid metabolism is closely linked to immune and inflammatory disorders. In autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, dysregulated phospholipid signaling exacerbates inflammation and immune cell infiltration. In cardiovascular disease, oxidized phospholipids promote atherosclerotic plaque formation. In cancer, phospholipid peroxidation-mediated ferroptosis can either suppress tumor progression or be exploited by the tumor microenvironment to evade immune surveillance. These findings provide a theoretical foundation for developing phospholipid-targeted therapies for inflammatory diseases.

“Although phospholipid-targeting drugs show promise in treating inflammation and cancer, several critical questions remain unresolved”, the authors remarked. Key challenges include elucidating the spatiotemporal dynamics of phospholipid metabolism in immune regulation as well as defining its precise role in specific cell types and tissue microenvironments. Future research should integrate single-cell omics and spatial transcriptomics to map phospholipid metabolic networks in immune microenvironments. Additionally, advances in high-resolution imaging and small-molecule drug design will improve the targeting specificity, further paving the way for metabolism-based therapies in inflammatory diseases and cancer.

“This review not only deepens our understanding of phospholipid-immune crosstalk, but also highlights exciting translational opportunities for next-generation immunometabolic therapeutics”, concluded the authors.

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Reference
DOI: 10.1007/s44466-025-00001-5

About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.
Website: https://link.springer.com/journal/44466

About Authors
Luke O’Neill
Prof. Luke O’Neill is the head of the Department of Biochemistry, Trinity College Dublin, and academic director of the Trinity Biomedical Sciences Institute. He has received the Royal Irish Academy Biochemistry Medal, the Irish Immunology Society Medal, the Royal Dublin Society/The Irish Times Boyle Medal for Scientific Excellence, and the Science Foundation Ireland Researcher of the Year Award. His research focuses on investigating molecular and cellular mechanisms of inflammation and innate immunity.

Juan Liu
Prof. Juan Liu is a professor at the Institute of Immunology, Naval Medical University/National Key Laboratory of Immunology and Inflammation. She has received the National Science Fund for Excellent Young Scholars and been selected as a Young Changjiang Scholar by the Ministry of Education. She serves as the chief scientist of the Youth Program of the National Key R&D Program of China and is awarded the Top 10 Scientific and Technological Progresses in Chinese Universities by the Ministry of Education. Her research focuses on metabolic regulation of innate immunity and molecular mechanisms of autoimmune diseases.

Funding information
This work was supported by National Natural Science Foundation of China (92374115, 82388201), National Key R&D Program of China (2023YFA1801400), CAMS Innovation Fund for Medical Sciences (2021-I2M-1–017), and China Postdoctoral Science Foundation (2023M740318).