Visomitin Attenuates Pathological Bone Loss by Reprogramming Osteoclast Metabolism via the STAT3/LDHB Axis.

Abstract

A persistently substantial energy demand and metabolic reprogramming endure throughout the entire course of osteoclastogenesis, accompanied by an intensified oxidative stress. Hence, balancing cellular energy metabolism and maintaining redox homeostasis offer potential for coordinating osteoclastogenesis and bone loss in pathological conditions. In the present study, we have discovered Visomitin, a novel antioxidant that specifically targets mitochondria, which efficiently decreases intracellular reactive oxygen species (ROS) levels, inhibits osteoclastogenesis, and impairs the function of bone resorption. Mechanistically, Visomitin directly targets signal transducer and activator of transcription 3 (STAT3), leading to the inhibition of its transcriptional activity and modulation of lactate dehydrogenase B (LDHB) expression levels, consequently triggering metabolic reprogramming and exerting antagonistic effects on osteoclasts. Furthermore, administration of Visomitin demonstrates marked protective effects against pathological bone loss in vivo. Given its established clinical safety profile in ophthalmologic applications, Visomitin emerges as a promising anti-resorptive agent for clinical translation. This study also unveils the STAT3/LDHB axis as a critical nexus linking mitochondrial redox regulation to osteoclast metabolism, providing a novel therapeutic strategy for osteoclast-driven bone diseases.