Pyroptosis in systemic lupus erythematosus and lupus nephritis: evidence grading, cellular crosstalk, and translational priorities
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.
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BibTeX
@article{fan2026pyroptosis,
title = {{Pyroptosis in systemic lupus erythematosus and lupus nephritis: evidence grading, cellular crosstalk, and translational priorities}},
author = {Jia Fan and Kaili Zheng and Li Hua and Xuelian Hong and Hongwei Du},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1976486},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1976486},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Pyroptosis in systemic lupus erythematosus and lupus nephritis: evidence grading, cellular crosstalk, and translational priorities
AU - Jia Fan
AU - Kaili Zheng
AU - Li Hua
AU - Xuelian Hong
AU - Hongwei Du
PY - 2026
DA - 2026/11/09
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1976486
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1976486
AB - 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.
SN - 1664-3224
ER -