Regulation of osteoclastogenesis and bone resorption by fatty acid metabolism: mechanisms and therapeutic opportunities

Bone remodeling is orchestrated by osteoclast-mediated resorption and osteoblast-mediated formation. Dysregulated hyperactivity of osteoclasts is a central driver of pathological bone loss in multiple osteolytic diseases, such as postmenopausal osteoporosis, rheumatoid arthritis, and peri-implant osteolysis. Although the core RANKL signaling cascade that governs osteoclast differentiation has been well characterized, accumulating evidence indicates that RANKL also triggers profound metabolic reprogramming during osteoclastogenesis, among which fatty acid (FA) metabolism has emerged as a critical regulator of osteoclast fate and function. In this review, we provide a comprehensive analysis of how FA metabolic pathways regulate osteoclast differentiation, fusion, and function. We first briefly introduce the core FA metabolic pathways relevant to osteoclasts, including FA uptake, FA oxidation, FA storage, de novo lipogenesis, and protein S-palmitoylation. We then examine their specific roles in osteoclastogenesis, focusing on the key regulators (namely FATP2, FABP4, CD36, FASN, ACC1, CPT1A, and DGAT1). Furthermore, we evaluate the translational potential of targeting these metabolic nodes for treating osteolytic diseases, and discuss key challenges, including paradoxical stage-dependent functions of FA oxidation, off-target and species-specific toxicities of systemic inhibitors, and the necessity of osteoclast-specific delivery strategies. Finally, we identify critical knowledge gaps and propose future directions. Collectively, targeting osteoclastic FA metabolism offers a promising, yet challenging, therapeutic avenue for osteolytic diseases.