Myofibroblast-transformed MSCs promote osteoclastogenesis via mitochondrial transfer in osteoradionecrosis of the jaws

• PDGFRβ + MSCs were critical drivers of bone marrow fibrosis in ORNJ. • Myofibroblast-transformed MSCs exhibited enhanced mitophagy in irradiated niches. • MSCs modulated osteoclast activation through mitochondrial transfer. Osteoradionecrosis of the jaws (ORNJ) presents a significant challenge in contemporary medicine. Despite advances in clinical treatments of antifibrotic therapies based on the radiation-induced fibroatrophy (RIF) theory, critical gaps remain in understanding the cellular mechanisms driving fibrosis progression and their connection to pathological bone remodeling. In this study, we identify mesenchymal stem cells (MSCs) as pivotal mediators of bone marrow fibrosis through their transformation into myofibroblasts. We demonstrate that these transformed MSCs enhance mitochondrial quality control via increased mitophagy, serving as a survival adaptation in irradiated microenvironments. Notably, mitochondria derived from myofibroblast-transformed MSCs promote osteoclast differentiation and orchestrate the pathological shift from fibrotic remodeling to osteolytic destruction. Our findings highlight the role of MSCs as critical drivers of bone marrow fibrosis and reveal novel intercellular mitochondria crosstalk between fibroblastic and osteoclastic lineages, offering valuable insights into the pathogenesis of ORNJ and emphasizing potential therapeutic strategies that target mitochondrial dynamics.