2. Academic Validation
  3. ZBTB16 controls the onset of Clostridium difficile colitis through the Pyrin inflammasome

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

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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