The immune thrombocytopenia therapeutic Avatrombopag alleviates osteoporosis by targeting NFATc1 signaling.

Osteoporosis is a systemic skeletal disorder characterized by increased osteoclast activity and bone loss, for which the clinical management remains an unmet need. Here, through in silico drug screening of an FDA-approved drug library, we identified Avatrombopag (Ava) - a thrombopoietin (TPO) receptor agonist approved for immune thrombocytopenia (ITP) - as a potent inhibitor of nuclear factor of activated T cells c1 (NFATc1), the master transcriptional regulator of osteoclastogenesis. Indeed, Ava significantly inhibited osteoclastogenesis in vitro, with significant inhibitory effects starting at a low concentration. Molecular docking analysis revealed that Ava binds with high affinity to NFATc1, forming hydrogen bonds with residues GLN-419 and ASP-417. This interaction was further validated by drug affinity responsive target stability (DARTS) and cellular thermal shift assay (CETSA). Moreover, Ava suppressed the expression of osteoclast marker genes (Nfatc1, Fos, Ctsk, Acp5) and inhibited resorptive function. To evaluate its therapeutic potential in vivo, Ava was administrated to ovariectomized (OVX)-induced osteoporotic mice. Micro-CT and histological analyses (H&E and TRAP staining) revealed that Ava protected against bone loss, accompanied by reduced osteoclast formation. Immunohistochemistry and qPCR assays of bone tissues further confirmed that Ava effectively downregulated NFATc1 expression. Collectively, our findings demonstrate that the ITP drug Ava may serve as a therapeutic option for osteoclast-related bone loss and potentially for ITP patients who also suffer from osteoporosis.