<p>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.</p>