<p>SLE is marked by dysregulated T cell activation, which consequently triggers the excessive generation of autoantibodies. Long non-coding RNAs (lncRNAs) may be associated with autoimmune and inflammatory diseases, and NIFK-AS1 has been found to be abnormally expressed in SLE. The aim of this study is to explore the abnormal expression and clinical role of NIFK-AS1 in SLE patients, and to investigate whether NIFK-AS1 regulates the expression of let-7f-5p to participate in the immune mechanism of SLE. This study included 88 healthy controls and 95 SLE patients and compared the expression levels of NIFK-AS1 in two groups. CD4 + T cells were extracted from the peripheral blood of patients in both groups, and the expression levels of NIFK-AS1 were overexpressed or knocked down through transfection technology. The impact of NIFK-AS1 on the activation of CD4 + T cells was also investigated. Furthermore, the relationship between the NIFK-AS1/let-7f-5p/STAT3 axis was verified through a dual-luciferase assay. Elevated levels of NIFK-AS1 were observed in both the serum and T cells of individuals with SLE. Furthermore, the expression of NIFK-AS1 is significantly correlated with the clinical indicators of SLE patients. NIFK-AS1 has a significant diagnostic effect on SLE. Functionally, the inhibition of NIFK-AS1 led to suppressed activation of healthy T cells and a reduction in the auto-reactivity of SLE-derived CD4 + T cells. Conversely, let-7f-5p inhibitor mitigated the inhibitory effects induced by NIFK-AS1 knockdown on CD4 + T cell activation. Furthermore, NIFK-AS1 promoted STAT3 expression by inhibiting let-7f-5p. The NIFK-AS1/let-7f-5p/STAT3 axis is significantly involved in T cell activation within SLE, thereby offering a promising therapeutic target for the management of this disease.</p>