High-efficient discovering the potent anti-Notum agents from herbal medicines for combating glucocorticoid-induced osteoporosis

https://doi.org/10.1016/j.apsb.2025.06.004

This new article publication from Acta Pharmaceutica Sinica B, discusses an efficient strategy for discovering anti-Notum compounds from herbal medicines.

Notum, a negative feedback regulator of the Wnt signaling, has emerged as a promising target for treating glucocorticoid-induced osteoporosis (GIOP). This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines (HMs) as novel anti-GIOP agents. Firstly, a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs. The results showed that Bu-Gu-Zhi (BGZ), a known anti-osteoporosis herb, potently inhibited Notum in a competitive-inhibition manner. To uncover the key anti-Notum constituents in BGZ, an efficient strategy was adapted via integrating biochemical, phytochemical, computational, and pharmacological assays. Among all identified BGZ constituents, three furanocoumarins were validated as strong Notum inhibitors, while 5-methoxypsoralen (5-MP) showed the most potent anti-Notum activity and favorable safety profiles. Mechanistically, 5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum. Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone (DXMS)-challenged MC3T3-E1 osteoblasts. In dexamethasone-induced osteoporotic mice, 5-MP strongly elevated bone mineral density (BMD) and improved cancellous and cortical bone thickness. Collectively, this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs, while 5-MP emerges as a promising anti-GIOP agent.

Keywords: Notum, NIR fluorogenic substrate, High-throughput screening, Glucocorticoid-induced osteoporosis (GIOP), A high-efficient platform, 5-Methoxypsoralen, Wnt signaling, Osteoblast differentiation

Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383525004010-ga1_lrg.jpg   

A high-efficient platform for discovering key anti-Notum constituents from HMs was constructed, while 5-MP was identified as a potent Notum inhibitor capable to activate the Wnt/β-catenin signaling pathway, showing good safety profiles and impressive anti-GIOP effects.

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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.

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CiteScore: 24.3

Impact Factor: 14.6 (Top 6 journal in the category of Pharmacology and pharmacy) 

JIF without self-citation: 13.8

ISSN 2211-3835

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Yuqing Song, Feng Zhang, Jia Guo, Yufan Fan, Hairong Zeng, Mengru Sun, Jun Qian, Shenglan Qi, Zihan Chen, Xudong Jin, Yunqing Song, Tian Tian, Zhi Qian, Yao Sun, Zhenhao Tian, Baoqing Yu, Guangbo Ge, High-efficient discovering the potent anti-Notum agents from herbal medicines for combating glucocorticoid-induced osteoporosis, Acta Pharmaceutica Sinica B, Volume 15, Issue 8, 2025, Pages 4174-4192, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2025.06.004