Gasdermin D-Mediated Pyroptosis in Systemic Lupus Erythematosus: Mechanisms and Therapeutic Potential

Pyroptosis plays a pivotal role in autoimmune and rheumatological pathogenesis, driving chronic inflammation and subsequent tissue damage in systemic lupus erythematosus (SLE). In this review, we conducted a comprehensive literature search across Medline/PubMed, EMBASE, Scopus, Web of Science, and the Directory of Open Access Journals (DOAJ) for peer-reviewed articles published through July 1, 2026. The search strategy used Boolean operators (AND, OR) to combine Medical Subject Headings (MeSH) terms for systemic lupus erythematosus, lupus, pyroptosis, and gasdermin D (GSDMD). This review summarizes the molecular basis of pyroptosis and gasdermin signaling, with a particular emphasis on GSDMD, and examines current evidence linking these pathways to SLE. Mechanistically, NLRP3 inflammasome activation leads to GSDMD-mediated membrane pore formation, facilitating the release of the proinflammatory cytokines IL-1β and IL-18. This process may contribute to the characteristic inflammatory cycle of SLE and correlate with clinical manifestations such as renal involvement. In autoimmune contexts, the dysregulation of key regulatory checkpoints within this pathway further exacerbates immune system dysfunction. Given that conventional therapeutic strategies in SLE primarily focus on symptom management, investigating novel pathways remains crucial. Consequently, this review highlights the potential involvement of pyroptosis in chronic inflammation, autoantigen exposure, and organ damage, as well as emerging treatment strategies targeting the NLRP3–caspase-1–GSDMD axis. Modulating this pathway through specific NLRP3 inhibitors, caspase-1 blockade, or molecules that inhibit GSDMD pore formation may represent a promising therapeutic avenue to suppress inflammation and mitigate organ damage, particularly in cases refractory to standard immunosuppressive therapies.