ZDHHC11-mediated palmitoylation alleviates chondrocyte senescence and serves as a therapeutic target for osteoarthritis [I]

Osteoarthritis (OA) is a chronic, degenerative whole-joint disorder that interferes with quality of life in older individuals. Here, we report a high expression of ZDHHC11 in articular chondrocytes, which is downregulated in the degenerated cartilage of aged mice and OA patients. ZDHHC11 prevents chondrocyte senescence and fosters cartilage anabolism, culminating in an improved OA phenotype. Mice with Zdhhc11 deletion (Zdhhc11fl/fl) exacerbate OA progression in a DMM model. Specifically, we identify ZDHHC11 as a key palmitoyltransferase, the depletion of which leads to GNB2-dependent E3 ubiquitin ligase-mediated proteasomal degradation of APOD. Mechanistically, ZDHHC11-mediated palmitoylation alleviates OA progression by deactivating the senescence-associated GATA4-P65 signaling pathway.