The gasdermin family in depression-associated neuroinflammation: established evidence, emerging mechanisms, and therapeutic perspectives
Year: 2026
Type: article
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.
Source: Frontiers in Immunology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225227703