High-efficient discovering the potent anti-Notum agents from herbal medicines for combating glucocorticoid-induced osteoporosis.
10.1016/j.apsb.2025.06.004
- Author:
Yuqing SONG
1
;
Feng ZHANG
1
;
Jia GUO
2
;
Yufan FAN
1
;
Hairong ZENG
1
;
Mengru SUN
1
;
Jun QIAN
3
;
Shenglan QI
1
;
Zihan CHEN
1
;
Xudong JIN
4
;
Yunqing SONG
1
;
Tian TIAN
1
;
Zhi QIAN
5
;
Yao SUN
3
;
Zhenhao TIAN
1
;
Baoqing YU
5
;
Guangbo GE
1
Author Information
1. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
2. Shi's Center of Orthopedics and Traumatology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
3. Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology & Department of Oral Implantology, Stomatological Hospital and Dental School, Tongji University, Shanghai 201203, China.
4. University of Oxford, Oxford OX3 7BN, UK.
5. Department of Orthopedics, the Seventh People's Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200137, China.
- Publication Type:Journal Article
- Keywords:
5-Methoxypsoralen;
A high-efficient platform;
Glucocorticoid-induced osteoporosis (GIOP);
High-throughput screening;
NIR fluorogenic substrate;
Notum;
Osteoblast differentiation;
Wnt signaling
- From:
Acta Pharmaceutica Sinica B
2025;15(8):4174-4192
- CountryChina
- Language:English
-
Abstract:
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.
