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Objective SLE is a multifaceted chronic inflammatory disorder characterised by a dysregulated immune response that involves various organ systems, with significant implications stemming from the type I interferon (IFN) signalling pathway in its pathogenesis. This study aimed to elucidate the contributory role of the IFN-induced protein 44-like ( IFI44L) gene in SLE progression and to investigate its transcriptional regulatory mechanisms.Methods We quantified IFI44L expression in peripheral blood mononuclear cells of patients with SLE through quantitative PCR (qPCR), and established an in vitro THP-1 cell model overexpressing IFI44L to assess its impact under IFN-α exposure using Cell Counting Kit-8 assays and flow cytometry. Additionally, we generated Ifi44l knockout mice and Pristane-induced lupus mice to evaluate the influence of IFI44L on immune phenotypes and organ functionality.Results Our findings demonstrated that IFI44L is significantly expressed in CD3+ and CD14+ lymphocytes in patients with SLE, and under heightened IFN conditions, it plays a role in promoting cell proliferation while inhibiting apoptosis. Importantly, Ifi44l knockout mice exhibited ameliorated clinicopathological features of lupus, showing reduced haematological and renal damage. Furthermore, we identified c-Jun as a transcriptional factor that directly targets the IFI44L promoter, specifically activated by IFN-α in CD14+ lymphocytes.Conclusions Our research indicates that IFN-α enhances IFI44L expression via c-Jun, underscoring its critical role in the pathogenesis of SLE and suggesting potential pathways for therapeutic intervention.