Pyroptosis in systemic lupus erythematosus and lupus nephritis: evidence grading, cellular crosstalk, and translational priorities
Year: 2026
Type: article
Abstract: Systemic lupus erythematosus (SLE) links persistent immune dysregulation to heterogeneous tissue injury, but the mechanisms that localise damage remain incompletely resolved. Pyroptosis is a gasdermin-mediated, pore-forming process that can connect nucleic-acid sensing and inflammasome activation to mediator release and tissue-cell dysfunction. Here, we evaluate the SLE and lupus nephritis (LN) literature along two independent axes: mechanistic evidence for pathway licensing, inflammasome activation, gasdermin execution, or terminal lysis, and disease relevance across non-lupus models, lupus models, patient-derived cells, human renal tissue, and longitudinal cohorts. Four conclusions emerge. First, execution-level evidence is confined to a few nodes, including oxidised mitochondrial DNA-driven GSDMD oligomerisation, myeloid caspase-11/GSDMD signalling, and GSDME-mediated tubular epithelial injury; most reported lupus “pyroptosis axes” demonstrate licensing or inflammasome activation only. Second, the direction of GSDMD function remains unresolved: pharmacological inhibition ameliorates experimental lupus, whereas genetic deficiency worsens autoimmunity, renal and pulmonary inflammation, and myeloid calcium homeostasis. Third, the tubulointerstitial compartment carries the strongest executor-level causal evidence in the kidney, whereas glomerular studies offer broader regulatory hypotheses but weaker execution-level proof. Fourth, no current biomarker is execution-specific, and no intervention has demonstrated executor target engagement in patients. We therefore present immune-tissue crosstalk as an evidence-graded framework rather than a demonstrated end-to-end circuit and define the spatial, longitudinal, and lineage-specific studies needed for mechanism-guided translation.
Source: Frontiers in Immunology
Authors: Jia Fan, Kaili Zheng, Li Hua, Xuelian Hong, Hongwei Du
Institution: Jinhua Central Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225643899