Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disease with complex pathogenic mechanisms. Mitochondrial function and programmed cell death (PCD) play important roles in SLE. This study aims to screen biomarkers related to mitochondrial function and PCD in SLE and analyze their underlying mechanisms.

SLE-related gene expression datasets were obtained from the GEO database, with three datasets merged into one as the training set. Genes related to mitochondrial function and PCD were sourced from the MitoCarta 3.0 database. Key genes were identified through bioinformatics analysis and machine learning algorithms. Their expression levels and diagnostic efficacy were validated using two independent SLE datasets as the validation set. The relationship between the diagnostic genes and immune cells was analyzed via CIBERSORT immune infiltration analysis. Diagnostic gene‑related miRNAs were predicted using online databases. Differentially expressed circRNAs were screened from SLE circRNA datasets, and interactions between circRNAs and miRNAs were predicted using circbank, ultimately constructing a circRNA‑miRNA‑mRNA ceRNA regulatory network.

From 448 differentially expressed genes in the SLE training set, two key genes, IFI27 and LAMP3, were identified through machine learning and weighted gene co‑expression network analysis (WGCNA). Enrichment analysis revealed that they were mainly enriched in pathways such as cell cycle, systemic lupus erythematosus, cytosolic DNA sensing pathway, Toll‑like receptor (TLR) signaling pathway, and NOD‑like receptor (NLR) signaling pathway. Immune infiltration analysis showed that compared with the normal group, 11 immune cells were differentially expressed; IFI27 was correlated with nine types of immune cells, and LAMP3 with ten types. The finally constructed circRNA‑miRNA‑mRNA ceRNA regulatory network consisted of 2 mRNAs, 5 miRNAs, and 4 circRNAs.

This study identified two biomarkers, IFI27 and LAMP3, related to mitochondrial function and programmed cell death that play important roles in SLE. In the future, IFI27 and LAMP3 have the potential to become important biomarkers for the diagnosis and treatment of SLE. Their roles in immune responses may provide new strategies for the treatment of SLE.