Compartment-specific roles of gasdermin D and E in photoreceptor degeneration: evidence and pharmacological implications
- 1Hunan University of Chinese Medicine
- 2Institute of Ophthalmology and Otolaryngology of Chinese Medicine
- 3Changsha Centre for Innovation in Traditional Chinese Medicine Techniques for the Prevention and Treatment of Retinal Diseases and Visual Function Protection
Abstract
Photoreceptor degeneration arises from diverse genetic and acquired insults, yet oxidative stress, mitochondrial dysfunction, and sterile inflammation repeatedly converge on membrane injury and irreversible cell loss. Inflammasome activation is frequently described as retinal pyroptosis, although upstream markers alone neither establish gasdermin-dependent lysis nor identify the executing cell. Rather than treating retinal pyroptosis as a single cell-autonomous pathway, we distinguish a myeloid gasdermin D (GSDMD) inflammatory relay from a photoreceptor-intrinsic gasdermin E (GSDME) lytic amplification program and evaluate potential interventions according to direct retinal evidence, cellular specificity, and translational readiness. GSDMD is best supported in microglia and subretinal macrophages, where inflammasome-caspase-1 signaling promotes cytokine and extracellular-vesicle release and can worsen secondary photoreceptor injury. Recent evidence in TREM2-deficient rd10 retina further supports GSDMD as a functional disease modifier, while remaining context specific. By contrast, GSDME has direct loss-of-function support in all-trans-retinal overload, in which caspase-3-dependent cleavage increases membrane rupture and is associated with mitochondrial oxidative burden and ferroptotic susceptibility. We compare NLRP3/caspase-1, interleukin-1, GSDMD pore, GSDME, and redox-directed strategies against five translational gates: target engagement, ocular exposure, cell specificity, delivery feasibility, and safety. This evidence-graded framework identifies promising pharmacological entry points while preserving the distinction between mechanistic plausibility and retinal target readiness.
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BibTeX
@article{deng2026compartmentspecific,
title = {{Compartment-specific roles of gasdermin D and E in photoreceptor degeneration: evidence and pharmacological implications}},
author = {Ying Deng and Yasha Zhou and Pai Zhou and Li Xiao and Jing Lu and Qinghua Peng and Yijing Yang},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1981060},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1981060/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Compartment-specific roles of gasdermin D and E in photoreceptor degeneration: evidence and pharmacological implications
AU - Ying Deng
AU - Yasha Zhou
AU - Pai Zhou
AU - Li Xiao
AU - Jing Lu
AU - Qinghua Peng
AU - Yijing Yang
PY - 2026
DA - 2026/10/29
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1981060
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1981060/full
AB - Photoreceptor degeneration arises from diverse genetic and acquired insults, yet oxidative stress, mitochondrial dysfunction, and sterile inflammation repeatedly converge on membrane injury and irreversible cell loss. Inflammasome activation is frequently described as retinal pyroptosis, although upstream markers alone neither establish gasdermin-dependent lysis nor identify the executing cell. Rather than treating retinal pyroptosis as a single cell-autonomous pathway, we distinguish a myeloid gasdermin D (GSDMD) inflammatory relay from a photoreceptor-intrinsic gasdermin E (GSDME) lytic amplification program and evaluate potential interventions according to direct retinal evidence, cellular specificity, and translational readiness. GSDMD is best supported in microglia and subretinal macrophages, where inflammasome-caspase-1 signaling promotes cytokine and extracellular-vesicle release and can worsen secondary photoreceptor injury. Recent evidence in TREM2-deficient rd10 retina further supports GSDMD as a functional disease modifier, while remaining context specific. By contrast, GSDME has direct loss-of-function support in all-trans-retinal overload, in which caspase-3-dependent cleavage increases membrane rupture and is associated with mitochondrial oxidative burden and ferroptotic susceptibility. We compare NLRP3/caspase-1, interleukin-1, GSDMD pore, GSDME, and redox-directed strategies against five translational gates: target engagement, ocular exposure, cell specificity, delivery feasibility, and safety. This evidence-graded framework identifies promising pharmacological entry points while preserving the distinction between mechanistic plausibility and retinal target readiness.
SN - 1663-9812
ER -