Angelic Acid Prevents RANKL-Induced Osteoclastogenesis Through Pathway-Biased Inhibition of MAPK–NFATc1 Signaling

Abstract Excessive osteoclast activity drives inflammatory bone loss in osteoporosis, rheumatoid arthritis, and periodontitis. Natural compounds represent promising therapeutic candidates with favorable safety profiles; however, few exhibit pathway-biased mechanisms of action. Here, we report that angelic acid, a naturally occurring unsaturated monocarboxylic acid, potently inhibits RANKL-induced osteoclastogenesis. This effect occurs with an IC₅₀ of 1.9 µM without cytotoxicity. Mechanistically, angelic acid preferentially suppressed MAPK signaling, including ERK, p38, and JNK phosphorylation. In contrast, NF-κB transcriptional activity remained unaffected, indicating pathway-biased inhibition. Consistent with impaired MAPK activation, angelic acid blocked NFATc1 nuclear translocation and significantly reduced expression of osteoclast-specific genes, including TRAP , cathepsin K , and Atp6v0d2 . These findings identify angelic acid as a novel inhibitor of osteoclast differentiation acting through MAPK-dependent regulation of NFATc1, providing a mechanistic foundation for therapeutic development in bone-resorptive diseases.