Galactose-modified small molecule modulator targets RORα to enhance circadian rhythm and alleviate periodontitis-associated alveolar bone loss

  • Bone Res. 2025 Oct 30;13(1):91. doi: 10.1038/s41413-025-00445-w.
Guangxia Feng  #  1  2  3 ,  Zhiwen Liao  #  4 ,  Yifan Wang  #  5  6 ,  Qingming Tang  1  2  3 ,  Nayun Li  1  2  3 ,  Cheng Li  1 ,  Yuqing Liu  1  2  3 ,  Renlong Liu  1  2 ,  Mingjian Cui  4 ,  Wenjie Fan  1  2  3 ,  Ying Yin  1  3 ,  Lingkui Meng  4 ,  Jing Zeng  4 ,  Zetao Chen  7 ,  Guanzheng Luo  8 ,  Peng Xiang  8 ,  Qian Wan  9 ,  Lili Chen  10  11  12  13
Affiliations
  • 1. Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 2. School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 3. Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, Hubei, China.
  • 4. Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, China.
  • 5. School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected].
  • 6. Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, Hubei, China. [email protected].
  • 7. Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, China.
  • 8. School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
  • 9. Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, China. [email protected].
  • 10. Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected].
  • 11. School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected].
  • 12. Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, Hubei, China. [email protected].
  • 13. Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangdong Research Center for Dental and Cranial Rehabilitation and Material Engineering, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 41168164 DOI: 10.1038/s41413-025-00445-w
Abstract

Circadian rhythm disorders are associated with dysfunction in inflammatory diseases, and targeted regulation of the circadian rhythm could serve as an intervention strategy. RORα/γ, as core components of circadian clock genes, positively modulate the key circadian molecule BMAL1. In this study, Gala-SR, a potent small-molecule compound designed to effectively regulate circadian rhythms, was synthesized through a monosaccharide modification prodrug strategy via a hydrolysable conjugation of galactose onto SR1078, an unique synthetic agonist of RORα/γ. Compared with SR1078, Gala-SR exhibited significantly greater aqueous solubility, cytocompatibility, pharmacokinetic characteristics and efficacy in the targeted activation of RORα. Importantly, Gala-SR ameliorated rhythm disorders by enhancing amplitude of the circadian rhythm both in vitro and in vivo. In circadian rhythm disordered mice with periodontitis, Gala-SR restored local circadian rhythm and mitigated inflammation in periodontal tissue in a circadian clock-dependent manner, and alleviated alveolar bone loss. Our study demonstrates that Gala-SR exhibits great promise in restoration of circadian rhythm and could potentially serve as a targeted therapeutic intervention for treating inflammatory diseases arising from disruptions in circadian rhythm. This work provides a feasible paradigm for the development and translational application of small molecule modulators targeting circadian rhythms.

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