2. Academic Validation
  3. Simvastatin Alleviates ConA-Induced Autoimmune Hepatitis by Inhibiting CD4+ T Cell Activation via Calcium-NFATC3 Pathway

Simvastatin Alleviates ConA-Induced Autoimmune Hepatitis by Inhibiting CD4+ T Cell Activation via Calcium-NFATC3 Pathway

  • Inflammation. 2026 Jan 30;49(1):72. doi: 10.1007/s10753-026-02462-1.
Xiyu Wang 1 2,  Tianhang Long 1 2,  Longyang Zhou 1 2,  Nan Xu 1 2,  Peiyang Fang 1 2,  Buer Li 3,  Haozhe Xu 1 2,  Guangyong Sun 1 2,  Dong Zhang 1 2 4 5,  Hua Jin 6 7
Affiliations

Affiliations

  • 1 Medical Research Center, Beijing Institute of Respiratory Medicineand Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China.
  • 2 Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China.
  • 3 Liver Research Center, Beijing Friendship Hospital, Capital MedicalUniversity, Beijing, 100050, China.
  • 4 Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing, 100069, China.
  • 5 General Surgery Department, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China.
  • 6 Medical Research Center, Beijing Institute of Respiratory Medicineand Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China. [email protected].
  • 7 Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China. [email protected].
PMID: 41618046 DOI: 10.1007/s10753-026-02462-1
Abstract

Although simvastatin plays a crucial role in lipid management, tumor therapy and acute liver injury, its potential effects in autoimmune hepatitis (AIH) has received limited investigative attention. Our study demonstrated that in the ConA-induced AIH model, HMG-CoA reductase (HMGCR), the pharmacological target of simvastatin (SIM), was significantly upregulated in T cells, particularly in CD4+ T cells. Furthermore, our results showed that simvastatin treatment in ConA-induced AIH model reduced the level of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and alleviated liver injury. Flow cytometric analysis revealed that simvastatin treatment promoted CD4+ T cell Apoptosis while significantly reducing the secretion of crucial inflammatory cytokines in vivo and vitro, including IL-17A, IL-6, IFN-γ, and TNF-α. To explore the underlying mechanisms, we performed transcriptome Sequencing on the CD4+ T cells from mice treated with or without simvastatin. RNA-sequencing analysis revealed the involvement of the calcium signaling pathway and transcription factor NFATC3 in the regulation of CD4+ T cells. qPCR and flow cytometry analyses further confirmed that simvastatin exerted its therapeutic effects by suppressing the calcium signaling pathway and downregulating the expression of nuclear factor of activated T cells 3 (NFATC3). Collectively, our study demonstrates that simvastatin alleviates CD4+ T cell inflammatory responses in AIH through calcium-dependent signaling pathway.

Keywords

Autoimmune hepatitis; Calcium influx; Mevalonate pathway; NFATC3; Simvastatin.

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