OXR1 is a dual redox–mitochondrial checkpoint governing osteoclast differentiation and bone loss in an osteoporosis mouse model

Osteoclasts are mitochondria-rich cells that rely on oxidative phosphorylation to fuel differentiation and bone resorption. Oxidative phosphorylation generates reactive oxygen species (ROS), which support signaling but can also threaten mitochondrial integrity. Oxidation Resistance 1 (OXR1) is a redox-responsive regulator involved in antioxidant defense, but its role in osteoclasts remains unclear. Here, we show that OXR1 is upregulated during mouse osteoclastogenesis and OXR1 mRNA is enriched in human osteoclasts. Knockdown of Oxr1 in mouse osteoclast precursors causes excessive ROS accumulation, mitochondrial damage, and impaired autophagic flux. Accordingly, myeloid-specific loss of Oxr1 results in defective osteoclast formation and increased bone mass in mice. Mechanistically, OXR1 binds the antioxidant response regulator KEAP1 and promotes KEAP1 association with the autophagy adaptor P62/SQSTM1, thereby supporting mitochondrial ubiquitination and mitophagic clearance. In an ovariectomy-induced osteoporosis mouse model, intraosseous AAV9-shRNA-mediated Oxr1 silencing or pharmacological OXR1 inhibition suppresses osteoclast activity and attenuates bone loss. Thus, our findings suggest OXR1 to be a dual-function regulator that buffers ROS and simultaneously orchestrates the autophagic clearance of damaged mitochondria during osteoclastogenesis, hinting at OXR1 as a potential target for preventing osteoclast‑driven bone loss. Osteoclasts need to manage reactive oxygen species by coordinating redox control and mitochondrial quality maintenance. Here, the authors identify OXR1 as a regulator of osteoclastogenesis and mitophagy, and show that genetic or pharmacological targeting of OXR1 attenuates bone loss in an osteoporosis mouse model.