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

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 (AA), a naturally occurring unsaturated monocarboxylic acid, potently inhibits RANKL-induced osteoclastogenesis. This effect occurs with an IC50 of 1.9 µM without cytotoxicity. Mechanistically, AA selectively suppressed RANKL-activated phosphorylation of ERK1/2, p38, and JNK (all three MAPK branches), while leaving NF-κB transcriptional activity unaffected. This preferential MAPK suppression disrupted downstream NFATc1 nuclear translocation, thereby preventing NFATc1-driven transcription of osteoclast-specific effector genes including TRAP, cathepsin K, and Atp6v0d2. These findings identify AA as a novel inhibitor of the RANKL–MAPK–NFATc1 axis, providing a mechanistic foundation for its therapeutic development in osteoporosis and other osteolytic diseases.