Photoreceptor degeneration, whether driven by inherited mutations in diseases such as retinitis pigmentosa or by acquired insults like retinal detachment and age-related macular degeneration, almost always ends the same way: irreversible loss of the light-sensing cells of the retina. A new mini review published in Frontiers in Pharmacology argues that the inflammatory processes behind this cell death have been too often lumped together under a single label, and that teasing them apart could change how future therapies are designed. The review, written by researchers at Hunan University of Chinese Medicine and affiliated institutes in Changsha, China, draws a sharp line between two pore-forming proteins of the gasdermin family, gasdermin D and gasdermin E, and assigns them to different cellular compartments within the degenerating retina.
The authors’ central concern is with the popular term pyroptosis, a form of inflammatory, gasdermin-mediated cell lysis. In retinal studies, the presence of inflammasome markers such as NLRP3, caspase-1, interleukin-1 beta, and interleukin-18 is frequently taken as proof that photoreceptors are dying by pyroptosis. The review counters that this reasoning is mechanistically incomplete. Upstream markers alone do not establish that a gasdermin pore has formed, nor do they identify which cell type is actually being lysed. Inflammasome activation may occur in resident immune cells while photoreceptors die secondarily, a distinction the authors say is critical for both explanation and treatment.
To bring order to a scattered literature, the review proposes a compartment-based framework. Gasdermin D is characterized as a predominantly myeloid inflammatory relay, operating in microglia and subretinal macrophages, where inflammasome-caspase-1 signaling promotes the release of cytokines and inflammatory extracellular vesicles that can worsen secondary photoreceptor injury. Gasdermin E, by contrast, is presented as a photoreceptor-intrinsic lytic amplifier, activated by caspase-3 within the light-sensing cells themselves and linking apoptotic stress to membrane rupture and ferroptotic susceptibility. The distinction, the authors argue, offers more explanatory and therapeutic value than treating retinal pyroptosis as one linear pathway.
The evidence for gasdermin D rests on several complementary lines of work. In photo-oxidative retinal damage, mice carrying a pore-impaired Gsdmd I105N variant showed better retinal function, greater photoreceptor survival, and lower inflammatory gene expression after injury. Crucially, gasdermin D-positive cells in the subretinal space were predominantly IBA1-positive microglia and macrophages, and the protein supported the release of interleukin-1 beta-containing extracellular vesicles, suggesting its main retinal role is propagating inflammation rather than directly executing photoreceptors. An instructive complication emerged, however: complete Gsdmd knockout did not reproduce all of the protection seen with the pore-impaired allele, hinting at compensatory mechanisms during long-term absence of the protein and arguing that knockout, cleavage inhibition, and pore blockade should not be treated as interchangeable interventions.
Retinal detachment illustrates why cellular ownership remains contested. One study detected gasdermin D cleavage and found that subretinal delivery of the inhibitory GSDMD-C domain reduced inflammatory signaling and photoreceptor degeneration, findings interpreted as compatible with photoreceptor pyroptosis. A later localization study, however, found that most early gasdermin D-N-positive cells after detachment were microglia, and that the caspase-1 inhibitor VX-765 suppressed microglial pyroptosis while indirectly preserving the outer nuclear layer. The review notes these results need not conflict, since the dominant gasdermin D-expressing compartment may shift with time and injury severity, but they demonstrate why whole-retina immunoblotting cannot assign pyroptosis to photoreceptors.
The strongest inherited-disease evidence for gasdermin D comes from a 2026 study in the Pde6b rd10 model. Global TREM2 deficiency increased inflammasome-associated signaling in retinal myeloid cells, including cleaved caspase-1, cleaved gasdermin D, and mature interleukin-1 beta. Global or Cx3cr1-directed Gsdmd loss, as well as disulfiram-mediated pore inhibition, mitigated photoreceptor loss in this genetically sensitized background. The review treats this as establishing a functional, context-specific role for gasdermin D while stressing that it does not yet show the protein is required in ordinary rd10 degeneration, nor that it acts within photoreceptors themselves.
Gasdermin E presents a different evidentiary picture. In light-exposed Abca4-null/Rdh8-null mice and atRAL-loaded 661W cells, models of all-trans-retinal overload, the reactive retinoid induced reactive oxygen species, JNK activation, mitochondrial disruption, caspase-3 cleavage, and gasdermin E-N fragment formation. The active fragment localized to the photoreceptor outer nuclear layer, and Gsdme deletion reduced membrane rupture, caspase-3 activation, and photoreceptor degeneration. The antioxidant N-acetylcysteine suppressed the caspase-3-gasdermin E response, placing oxidative stress upstream of this lytic conversion. The review grades this as the strongest direct photoreceptor-intrinsic evidence, while cautioning that it derives from a single disease paradigm.
A 2025 study extended the model further, showing that Gsdme deletion reduced mitochondrial reactive oxygen species, iron accumulation, and lipid peroxidation after all-trans-retinal overload, while the mitochondrial antioxidant MitoTEMPO attenuated photoreceptor ferroptosis and retinal atrophy. The authors interpret this as support for a gasdermin E-dependent increase in mitochondrial oxidative burden and ferroptotic susceptibility, but they emphasize that direct mitochondrial pore formation by the gasdermin E-N fragment has not been proven as the causal step in photoreceptors. Generalization also requires caution, since comparable photoreceptor-specific loss-of-function data are not yet available in inherited models such as rd10.
On the pharmacological side, the review evaluates NLRP3/caspase-1 inhibition, interleukin-1 pathway modulation, direct gasdermin D pore blockade, gasdermin E-directed strategies, and redox or JNK-directed interventions against five translational gates: target engagement, ocular exposure, cell specificity, delivery feasibility, and safety. Upstream inflammasome inhibition is the most mature pharmacologically, with genetic Nlrp3 deficiency and caspase-1 blockade protecting photoreceptors in P23H, photo-oxidative, and detachment paradigms, but these interventions do not establish which gasdermin executes membrane injury. Disulfiram, which blocks pore formation, reduced gasdermin D oligomerization and photoreceptor loss in the TREM2-deficient rd10 retina, providing rare retinal target-engagement evidence, though the sensitized genetic context does not establish efficacy in unmodified disease and no compound yet has a validated ocular exposure-response relationship.
Gasdermin E remains a less mature drug target, with no selective pore inhibitor validated in retinal tissue and pharmacological efforts acting mainly upstream through caspase-3 or oxidative stress, each carrying potential safety concerns. The review concludes that the most credible programs will match executor, cell type, disease stage, and delivery route while demonstrating retinal target engagement and functional rescue, and calls for cell-resolved active-fragment localization, acute knockdown or conditional deletion with rescue experiments, and lytic readouts integrated with apoptosis and ferroptosis measurements in the same experiments. Human translation, the authors suggest, will require retinal organoids, donor tissue, and biomarkers that distinguish executor activation from general inflammation before efficacy trials are attempted.
Subject of Research: Compartment-specific roles of gasdermin D and gasdermin E in photoreceptor degeneration and their pharmacological implications
Article Title: Compartment-specific roles of gasdermin D and E in photoreceptor degeneration: evidence and pharmacological implications
Article References: Deng, Y., Zhou, Y., Zhou, P., Xiao, L., Lu, J., Peng, Q., & Yang, Y. (2026). Compartment-specific roles of gasdermin D and E in photoreceptor degeneration: evidence and pharmacological implications. Frontiers in Pharmacology, 17, Article 1981060. https://doi.org/10.3389/fphar.2026.1981060
Image Credits: AI Generated
DOI: 10.3389/fphar.2026.1981060
Keywords: gasdermin D, gasdermin E, photoreceptor degeneration, pyroptosis, inflammasome, microglia, ferroptosis, retinitis pigmentosa, NLRP3, retinal neuroinflammation, caspase-1, oxidative stress
News Source: Ophelia Keating. (October 30, 2026). Gasdermin D and E Play Distinct Roles in Photoreceptor Degeneration. Scienmag.
