Spatial lipidome and transcriptome profiling reveals stratified lipid architecture in human articular cartilage

Lipids, as a class of endogenous biomaterials, are essential for regulating tissue properties and homeostasis. Articular cartilage is an anisotropic tissue that exhibits spatially organized tissue functions and lipid metabolism, and its microenvironment is sensitive to lipid-mediated regulation. However, the spatial lipid composition and its functional significance in cartilage pathophysiology remain elusive. In this study, we performed spatial lipidomic and transcriptomic analyses on healthy and diseased human articular cartilage. We demonstrate a layer-dependent lipid composition mainly in the extracellular matrix and chondrocyte region, and the stratified lipid architecture aligns with region-specific gene expression and cellular phenotypes. The tissue near the cartilage surfaces is enriched with phospholipids and genes relevant to matrix secretion and lipid transport, whereas the tissue adjacent to subchondral bone, is featured by lyso-phospholipids and genes related to biomineralization. Moreover, we highlight ceramide (CER)'s role in mediating chondrocyte secretion and its potential protective function in early osteoarthritis (OA), suggesting that location-specific lipid diversity may contribute to the regulation of cartilage function. This study not only advances understanding of cartilage pathophysiology, but also provides a material-level blueprint for developing more biomimetic cartilage engineering strategies.