Targeted protein degradation in inflammatory bone diseases: Mechanistic basis and therapeutic opportunities

Inflammatory bone diseases (IBDs) are characterized by dysregulated immune responses and disrupted bone homeostasis, driving chronic inflammation and progressive bone destruction. Preclinical studies have established the therapeutic potential of targeting key inflammatory signaling molecules to mitigate pathological bone resorption. However, translating these breakthroughs into clinical practice faces significant challenges. Targeted protein degradation (TPD) represents a revolutionary therapeutic paradigm shift by exploiting the endogenous ubiquitin-proteasome system or autophagy-lysosome pathway to achieve selective elimination of pathogenic proteins. Recent advances highlight the immense potential of TPD for treating IBDs. This review summarizes the current understanding of the core pathological mechanisms of IBDs, while synthesizing the rapid evolution of TPD-based therapeutic approaches. Particularly, by highlighting innovative TPD strategies targeting critical molecular drivers of IBDs and reviewing promising carriers for bone-targeted delivery, this review underscores the significant clinical potential of TPD for IBDs treatment.