Emerging roles of the metabolite succinate in bone-related diseases.

Bone-related diseases, including osteoporosis (OP), osteoarthritis (OA), rheumatoid arthritis (RA), fracture, and periodontitis, significantly impact human health. Succinate, primarily known as a metabolic intermediate in the tricarboxylic acid (TCA) cycle, has emerged as a regulator of cellular functions beyond its metabolic role. Under stress, succinate accumulates in mitochondria and acts as a signaling molecule, modulating cellular processes. Notably, succinate activates angiogenesis and inflammation by stabilizing hypoxia-inducible factor-1α (HIF-1α). Moreover, it influences various pathophysiological processes by interacting with the succinate receptor 1 (SUCNR1), thereby impacting immune response, inflammation, cancer metastasis, and bone homeostasis. The multifaceted roles of succinate as a signaling molecule vary depending on its cellular location and concentration. Recent metabolomic analyses have revealed elevated succinate levels in bone-related diseases, indicating its potential association with these conditions. The objective of this review is to elucidate the impacts of succinate on different bone-related diseases and to discuss potential therapeutic targets and drug molecules based on its mechanisms of action.