BP-1-102 inhibits multiple pathways of NFATc1 activation to alleviate osteoporosis and downregulate osteoclast differentiation in ovariectomized mice
- Biochem Biophys Res Commun. 2026 Sep 3:829:154040. doi: 10.1016/j.bbrc.2026.154040.
- 1. Department of Emergency Surgery, The First Affiliated Hospital of Zhengzhou University, Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China.
- 2. Emergency Department, The People's Hospital of Xindu District, Chengdu City, Chengdu, Sichuan, 610500, China.
- 3. Emergency Medicine, The Sixth People's Hospital of Huizhou, Huizhou, Guangdong, 516211, China.
- 4. Department of Emergency Surgery, The First Affiliated Hospital of Zhengzhou University, Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China. Electronic address: [email protected].
Signal transducer and activator of transcription 3 (STAT3) activates nuclear factor of activated T cells 1 (NFATc1), a key regulator of osteoclastogenesis. This study investigated the STAT3 Inhibitor BP-1-102 in receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation from bone marrow macrophages (BMMs). BP-1-102 (2.5/5 μM) suppressed osteoclast formation and specific gene expression without cytotoxicity, while inhibiting STAT3 phosphorylation and NFATc1. Gene ontology analysis revealed enrichment in osteoclast differentiation and mitogen-activated protein kinase (MAPK) pathways. BP-1-102 downregulated the c-Fos/NFATc1 axis by suppressing MAPK and NF-κB signaling. In ovariectomized mice, BP-1-102 attenuated bone loss, reduced osteoclast numbers (≥3 nuclei), and inhibited STAT3/p38 phosphorylation. In summary, BP-1-102 rescues bone loss by targeting p-STAT3/MAPK/NF-κB signaling, demonstrating therapeutic potential for osteoporosis.