From lipotoxicity to pan-lipotoxicity
Yiping Cheng, Shanshan Shao, Zhen Wang, Qingbo Guan, Huaxue Li, Guodong Liu, Haiqing Zhang, Xiude Fan, Jiajun Zhao · Cell Discovery · 2025
In 1994, John Denis McGarry introduced the concept of “lipotoxicity”, defining it as the cellular damage and dysfunction of tissues and organs caused by the ectopic accumulation of triglycerides and free fatty acids in non-adipose tissues 1 . At the time, due to the limitations of detection techniques and conceptual understanding, the concept of “lipotoxicity” originally encompassed only triglycerides and free fatty acids, was confined to ectopic lipid accumulation as its primary manifestation, and was considered to exert toxic effects solely through localized pathological changes in specific tissues and organs. This narrow perspective restricted the understanding of the pathophysiological mechanisms, preventive strategies, and therapeutic approaches for lipid metabolism dysfunction-associated disorders. To address these limitations, we propose the concept of “pan-lipotoxicity”, which encompasses systemic cellular damage and tissue and organ dysfunction caused by lipid accumulation or imbalances in subcomponent proportions, lipoprotein metabolism disorders, and abnormal fat distribution or function. This new term will promote a paradigm shift in etiology research, from focusing on “single lipid components” to a “lipid metabolism panorama”, and in diagnostic and treatment models, from “single disease management” to “comorbid collaborative prevention and treatment”. This shift will lay the foundation for mechanistic studies, biomarker identification, and the diagnosis and treatment of lipid metabolic dysfunction-associated diseases.