Systemic lupus erythematosus (SLE) is a multifaceted dautoimmune disease driven by complex interactions among genetic, environmental, and sex-related factors. Central to its pathogenesis are type I interferons (IFN-I) and autoantibodies that target nucleic acids and nucleic acid-binding proteins. These mediators, often triggered by environmental stimuli in genetically susceptible individuals, promote sustained immune activation and chronic inflammation. Despite advances in understanding the immunological landscape of SLE, the precise initiating triggers and early molecular events remain incompletely defined. Recent studies have highlighted the destabilization of innate immune cells, particularly dendritic cells and monocytes, as critical early events in the pathogenesis of SLE. These alterations precede and potentially initiate the downstream activation of autoreactive lymphocytes. This review provides an updated synthesis of key epidemiological findings, emerging pathogenic mechanisms, potential therapeutic targets, and advances in translational and clinical research. Particular attention is given to recent insights into disease triggers and early pathological processes, especially the destabilization of innate immune cells. By consolidating these advances, this review aims to refine our understanding of the early immune dysregulation in SLE and to support the development of more precise, mechanism-based therapeutic strategies.