OBJECTIVE: To investigate the role of senescent epidermal basal cells in cutaneous lupus erythematosus (CLE) pathogenesis using skin samples from patients with CLE and a mouse model of systemic lupus erythematosus (SLE). METHODS: Cellular senescence profiling utilized datasets from the NCBI Gene Expression Omnibus database and Accelerating Medicines Partnership® (AMP®) Phase 1-Metro. Gene array data from GSE184989 (CLE: n = 68, control: n = 4), single-cell RNA sequencing data from GSE186476 (CLE: n = 7, control: n = 14), and AMP® Phase 1-Metro (SLE: n = 17) were utilized. In vitro experiments further examined the expression of p21 RESULTS: p21 CONCLUSION: Senescent cells create a microenvironment that directs cytotoxic T-cell-mediated responses against normal epidermis in CLE, contributing to disease pathology. Targeting senescent cells and their signalling pathways may offer novel therapeutic strategies for CLE and SLE skin lesions.