TTC26 scaffolds MINDY3-mediated RACK1 deubiquitination to drive osteoclastogenesis and pathological bone resorption

Background: Osteoclast overactivation is a central driver of bone metabolic disorders such as osteoporosis, and novel drug targets for these diseases continue to be actively explored. Scaffold proteins, which enhance the specificity of deubiquitinase (DUB)-substrate interactions, have emerged as promising therapeutic targets for the sustained management of chronic diseases. Intraflagellar transport (IFT) proteins, recognized for their scaffolding roles in cellular signaling, are increasingly implicated in bone remodeling. However, their therapeutic potential for bone metabolic disorders remains to be fully elucidated. Methods: ) in ovariectomized (OVX) mice, we validated its therapeutic potential as a novel target for osteoporosis intervention. Results: successfully alleviates trabecular bone loss in ovariectomized (OVX) mice. Conclusion: Our findings uncover a novel role for TTC26 in bone homeostasis and elucidate its molecular mechanism in driving osteoclastogenesis by scaffolding MINDY3-mediated deubiquitination of RACK1. Translational potential: This study holds clear clinical translational prospects: 1) TTC26 may serve as a novel biomarker for osteoporosis diagnosis; 2) Its functional residues provide precise targets for developing small-molecule inhibitors; 3) The scaffold protein regulatory paradigm offers a new model that can be referenced for treating other bone metabolic diseases.