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Nlrp12-driven PANoptosis exacerbates liver injury in ConA-induced autoimmune hepatitis

Genes & Immunity (2026)Cite this article

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Abstract

Autoimmune hepatitis (AIH) involves chronic liver injury from abnormal immune responses, leading to hepatocyte death and inflammation. Currently, the role of pyroptosis in AIH has not been fully elucidated. Emerging evidence indicates that Nlrp12, a cytosolic sensor of damage-associated molecular patterns (DAMPs), participates in inflammasome assembly and pyroptotic signalling. Therefore, this study aims to investigate the role of Nlrp12 in AIH. Using a concanavalin A (ConA)-induced AIH mouse model, we observed that ConA challenge significantly upregulated Nlrp12 expression in liver tissues. Genetic ablation of Nlrp12 improved survival rates, lowered serum aminotransferase levels, reduced pro-inflammatory cytokine production, and ameliorated histological liver damage. Further studies revealed that Nlrp12 drives the assembly of PANoptosomes (including ASC, RIPK3, and Caspase-8), promoting the release of PANoptosis-related proteins and inflammatory factors. The RIPK3 inhibitor GSK-872 blocked PANoptosome formation, mitigating liver injury and inflammation. These findings unveil a previously unrecognized role for Nlrp12 in aggravating immune-mediated liver injury via PANoptosis activation, highlighting the Nlrp12-PANoptosis axis as a promising therapeutic target for AIH.

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Fig. 1: Analysis of Nlrp12 expression in ConA-induced AIH murine models.
Fig. 2: Nlrp12 ablation attenuates ConA-induced hepatic injury and suppresses proinflammatory responses.
Fig. 3: Nlrp12 ablation suppresses ConA-induced upregulation of the expression of PANoptosis markers in AIH mice.
Fig. 4: Nlrp12 drives ConA-induced AIH pathology via PANoptosome assembly.
Fig. 5: Pharmacological inhibition of RIPK3 disrupts PANoptosome assembly and ameliorates ConA-induced liver injury.

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Data availability

Data from this study were made available through reasonable requests to the corresponding author. No datasets were generated or analysed during the current study.

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Acknowledgements

We acknowledge all individuals who contributed to this research and appreciate the funding that supported this research.

Funding

This study was supported by the National Natural Science Foundation of China (No.82170645), Department of Science and Technology of Sichuan Province (CN) (No.2024NSFSC0735), CMC Excellent-talent Programme (No.2024kjTzn04), the Scientific Research and Innovation Fund for Postgraduate of Chengdu Medical College (No. YCX2025-01-71) and the Research Fund of Chengdu Medical College (No. CYZYB25-10).

Declarations

All authors have made significant contributions to the conception, design, analysis, and/or interpretation of the work presented in this manuscript. Furthermore, all authors have thoroughly reviewed and approved the final version of the manuscript. They fully agree with its content and the decision to submit it for consideration.

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Author notes

  1. These authors contributed equally: Jun Lin, Kaiyu Feng, Feiyang Wang

Authors and Affiliations

  1. Department of General Surgery, Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China

    Jun Lin, Kaiyu Feng, Feiyang Wang, Xingyan Luo & Chunfen Mo

  2. Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China

    Jun Lin, Feiyang Wang, Ziqi Zheng, Xingyan Luo & Chunfen Mo

  3. School of Biosciences and Technology, Chengdu Medical College, Chengdu, China

    Kaiyu Feng & Chunfen Mo

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  1. Jun Lin
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Contributions

JL: Investigation, Data curation, Methodology, Writing-original draft. KYF: Investigation, Formal analysis, Methodology, Writing-original draft. FYW: Investigation, Formal analysis, Methodology. ZQZ: Validation, Methodology. XYL: Writing-review & editing, Project administration, Conceptualization. CFM: Writing-review & editing, Supervision, Funding acquisition, Conceptualization. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Xingyan Luo or Chunfen Mo.

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Competing interests

The authors declare no competing interests.

Ethical approval

All animal experiments were conducted following the Guide for the Care and Use of Laboratory Animals and approved by the Ethics Committee of Chengdu Medical College (Approval No.CMC-IACUC-2022052).

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All authors have read and approved the final version of the manuscript and agree to its publication. Informed consent was obtained from all participants involved in the study.

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Lin, J., Feng, K., Wang, F. et al. Nlrp12-driven PANoptosis exacerbates liver injury in ConA-induced autoimmune hepatitis. Genes Immun (2026). https://doi.org/10.1038/s41435-026-00386-2

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