E3 ubiquitin ligases in bone homeostasis: from regulatory mechanisms to skeletal diseases and therapeutic targeting.

E3 ubiquitin ligases are key determinants of substrate specificity within the ubiquitin-proteasome system and have emerged as important regulators of skeletal biology. Although traditionally classified into RING-, HECT-, and RBR-type families based on structural features, their roles in bone homeostasis are more clearly understood when examined in the context of specific skeletal regulatory processes. In this review, we briefly outline major E3 ligase families and the updated human E3 ligase landscape, and then discuss how representative E3 ligases regulate osteoblast differentiation, osteoclast differentiation, cartilage homeostasis, and bone remodeling. A central concept emerging from current evidence is that E3 ligases converge on critical regulatory nodes that govern skeletal cell fate and tissue-level remodeling. In osteogenesis, multiple E3 ligases control RUNX2 stability, transcriptional activity, and associated signaling pathways, including the BMP/SMAD and PI3K/Akt pathways. In osteoclast differentiation, E3 ligases primarily modulate TRAF6-dependent signaling and NF-κB activation, thereby influencing bone resorption. Beyond these lineage-specific roles, E3 ligases also participate in higher-order processes such as osteoblast-osteoclast coupling, osteoimmune regulation, mitochondrial quality control, and cartilage matrix homeostasis, highlighting their roles as process-level regulators of skeletal homeostasis. We further summarize how dysregulation of E3 ligase-mediated pathways contributes to common skeletal disorders, including osteoporosis, inflammatory bone loss, degenerative diseases, and therapy-associated complications. Finally, we discuss emerging pharmacological strategies targeting E3 ligases and E3-dependent pathways, including modulation of ubiquitination signaling and targeted protein degradation. Collectively, this review underscores the central roles of E3 ubiquitin ligases in integrating skeletal regulation and highlights their potential as therapeutic targets in bone-related diseases.