ZBTB16 controls the onset of Clostridium difficile colitis through the Pyrin inflammasome

  • Pharmacol Res. 2026 Mar:225:108133. doi: 10.1016/j.phrs.2026.108133.
Shuhui Li  1 ,  Jingjing He  2 ,  Huxidanmu Tuoheniyazi  3 ,  Junrui Ma  4 ,  Zhenyu Li  5 ,  Juanjuan Zheng  6 ,  Yuxin Wang  7 ,  Xiupan Gao  8 ,  Xiaobao Yang  9 ,  Danping Liu  10 ,  Yanan Zhao  11 ,  Tongxuan Su  12 ,  Yibing Peng  13 ,  Dakang Xu  14 ,  Xuefeng Fei  15
Affiliations
  • 1. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; College of Health Sciences and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
  • 2. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; College of Health Sciences and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
  • 3. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; College of Health Sciences and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
  • 4. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; College of Health Sciences and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
  • 5. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; College of Health Sciences and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
  • 6. Blood Transfusion Department, Qilu Hospital of Shandong University Dezhou Hospital, Dezhou, 253000, China. Electronic address: [email protected].
  • 7. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; College of Health Sciences and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
  • 8. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; College of Health Sciences and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
  • 9. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; College of Health Sciences and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
  • 10. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; College of Health Sciences and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
  • 11. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; College of Health Sciences and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
  • 12. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; College of Health Sciences and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
  • 13. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; College of Health Sciences and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
  • 14. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; College of Health Sciences and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
  • 15. Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China; College of Health Sciences and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: [email protected].
PMID: 41666999 DOI: 10.1016/j.phrs.2026.108133
Abstract

Clostridium difficile Infection (CDI) is a leading cause of antibiotic-associated diarrhea and pseudomembranous colitis, and there remains a significant unmet need for therapies specifically targeting C. difficile. The Pyrin inflammasome, activated by Bacterial toxins, plays a critical role in driving macrophage-mediated intestinal inflammation during CDI. In this study, we report that myeloid-specific deficiency of Zbtb16 protects mice from C. difficile-induced colitis by attenuating IL-1β-dependent inflammatory signaling. Mechanistic studies revealed that Zbtb16 deletion disrupts ASC oligomerization and speck formation, thereby selectively inhibiting inflammasome assembly and reducing mature IL-1β production in macrophages stimulated with C. difficile culture supernatant or purified TcdB toxin. Importantly, pharmacological degradation of ZBTB16 using the Cereblon E3 Ligase modulating drug CC-3060 significantly ameliorated colitis severity in a murine model of CDI. Our findings establish ZBTB16 as a key regulator of Pyrin inflammasome activation in macrophages, highlighting the therapeutic promise of ZBTB16 degradation as a novel strategy for treating CDI.

Keywords
ASC; Clostridium difficile; Colitis; Inflammasome; ZBTB16.
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