The gasdermin family in depression-associated neuroinflammation: established evidence, emerging mechanisms, and therapeutic perspectives
4 affiliations
- 1Central Laboratory, The First Hospital of Hebei Medical University
- 2Computer Network Information Center, Chinese Academy of Sciences
- 3Department of Otorhinolaryngology, The Second Hospital of Shijiazhuang
- 4Department of Gynecology Medicine, The First Hospital of Hebei Medical University
Abstract
Depression is a highly heterogeneous psychiatric disorder and represents a major public health burden. Its pathophysiology involves interacting alterations in neural, immune, metabolic, and psychosocial processes, and neuroinflammatory abnormalities appear to be particularly relevant in biologically defined subsets of patients and experimental contexts. In recent years, pyroptosis, a gasdermin-mediated form of inflammatory membrane permeabilization and lytic cell death, has attracted increasing attention as a potential link between cellular stress, immune activation, and depression-associated neuroinflammation. Current evidence is predominantly preclinical and has focused mainly on the NLRP3/caspase-1/GSDMD pathway, with depression-specific evidence being strongest for GSDMD. Importantly, however, the level of experimental support varies substantially across studies, ranging from changes in inflammasome and pyroptosis-related markers to detection of active gasdermin fragments and genetic or functional validation. In contrast, the potential involvement of other gasdermin family members remains less well established. GSDME represents a comparatively plausible emerging candidate because caspase-3-mediated cleavage can redirect apoptotic signaling toward inflammatory lytic cell death under appropriate cellular conditions. By comparison, the proposed roles of GSDMC, GSDMB, and GSDMA currently rely more heavily on mechanistic evidence from other neurological, immune, infectious, neoplastic, or barrier-associated conditions. In this review, we integrate current findings across the gasdermin family while explicitly distinguishing depression-specific evidence from mechanistic extrapolation. We further evaluate the evidence according to disease context, cell type, gasdermin cleavage, pore formation, functional cell death, and causal validation. This framework aims to clarify what is currently established, what remains biologically plausible, and which experiments are required to determine whether non-GSDMD gasdermins contribute to depression-associated neuroinflammation.
Related
- Regional Similarity to Sex-Typical Young Adult Brain Architecture is a Longitudinal Correlate of Neuroinflammation and Depression in Later Adulthood
- The neuroimaging correlates of depression established across six large-scale population datasets
- The cochlear macrophage in presbycusis: inflammaging, neuroinflammation, and targets for therapeutic modulation
- The cGAS-STING pathway in traumatic brain injury: mechanisms of neuroinflammation and therapeutic strategies
- Molecular Signatures of HIV-Induced Neuroinflammation and Neurodegeneration in Human Cerebral Organoids: Identification of Therapeutic Targets for NeuroHIV.
BibTeX
@article{luo2026gasdermin,
title = {{The gasdermin family in depression-associated neuroinflammation: established evidence, emerging mechanisms, and therapeutic perspectives}},
author = {Yang Luo and Ziming Liu and Huiqin Li and Bianling Xu and Xiaoyan Deng and Xueping Liu},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.1987982},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1987982/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The gasdermin family in depression-associated neuroinflammation: established evidence, emerging mechanisms, and therapeutic perspectives
AU - Yang Luo
AU - Ziming Liu
AU - Huiqin Li
AU - Bianling Xu
AU - Xiaoyan Deng
AU - Xueping Liu
PY - 2026
DA - 2026/11/04
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1987982
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1987982/full
AB - Depression is a highly heterogeneous psychiatric disorder and represents a major public health burden. Its pathophysiology involves interacting alterations in neural, immune, metabolic, and psychosocial processes, and neuroinflammatory abnormalities appear to be particularly relevant in biologically defined subsets of patients and experimental contexts. In recent years, pyroptosis, a gasdermin-mediated form of inflammatory membrane permeabilization and lytic cell death, has attracted increasing attention as a potential link between cellular stress, immune activation, and depression-associated neuroinflammation. Current evidence is predominantly preclinical and has focused mainly on the NLRP3/caspase-1/GSDMD pathway, with depression-specific evidence being strongest for GSDMD. Importantly, however, the level of experimental support varies substantially across studies, ranging from changes in inflammasome and pyroptosis-related markers to detection of active gasdermin fragments and genetic or functional validation. In contrast, the potential involvement of other gasdermin family members remains less well established. GSDME represents a comparatively plausible emerging candidate because caspase-3-mediated cleavage can redirect apoptotic signaling toward inflammatory lytic cell death under appropriate cellular conditions. By comparison, the proposed roles of GSDMC, GSDMB, and GSDMA currently rely more heavily on mechanistic evidence from other neurological, immune, infectious, neoplastic, or barrier-associated conditions. In this review, we integrate current findings across the gasdermin family while explicitly distinguishing depression-specific evidence from mechanistic extrapolation. We further evaluate the evidence according to disease context, cell type, gasdermin cleavage, pore formation, functional cell death, and causal validation. This framework aims to clarify what is currently established, what remains biologically plausible, and which experiments are required to determine whether non-GSDMD gasdermins contribute to depression-associated neuroinflammation.
SN - 1664-3224
ER -