Lipid Networks in Osteoarthritis: Context-Dependent Drivers, Hallmarks of Aging, and Clinical Translation.

Abstract

Osteoarthritis (OA) is an age-related condition affecting the entire joint. Abnormal lipid regulation may act as a trigger for disease onset, or result from inflammation or mechanical injury; alternatively, it may merely manifest as a detectable signal without any direct mechanistic significance. Given that causality cannot be determined based on abundance alone, we propose a compartment-cell temporal framework: pathogenic effects may arise when lipid composition, flux or localisation exceed the tissue's adaptive capacity. Experimental evidence plays a causal role for certain cholesterol and fatty acid pathways, whilst human lipid research remains at the stage of exploring associations. Lipid stress, through dysregulation of organelles such as the endoplasmic reticulum and mitochondria, converges with common features of joint ageing-including cellular senescence, mitochondrial dysfunction, imbalances in autophagy and proteostasis, inflammation, and alterations in signalling-and may reconcile previous conflicting findings in areas such as apolipoprotein E and fatty acid oxidation. At the translational level, weight loss and metabolic management are feasible short-term strategies, and the prospects for lipid stratification are promising; however, testing has not yet met clinical diagnostic standards, and lipid nanoparticles have not yet been established as a therapeutic method. At present, they should be regarded as delivery vehicles; challenges such as joint preservation, deep tissue delivery, and safety still need to be overcome, and validation in human tissue is required. In summary, lipid research contributes to the classification and treatment of OA, but a strict distinction must be made between the maturity of causal evidence and mere correlation.