Pyroptosis-associated inflammasome activation contributes to scleral remodeling in experimental myopia

To explore whether pyroptosis, an inflammatory type of programmed cell death, participates in the initiation and progression of myopia, and to further elucidate its regulatory role in scleral remodeling.

Scleral tissues from form-deprivation myopia (FDM) mouse models were subjected to transcriptome sequencing to screen inflammatory and cell death-related molecular characteristics. Differentially expressed gene analysis and pathway enrichment analysis were adopted to identify pyroptosis-related signaling pathways. Meanwhile, human scleral fibroblasts were treated with complement component 3a (C3a) to construct an in vitro inflammatory cell model. Western blot, immunofluorescence staining, lactate dehydrogenase (LDH) release assay and transmission electron microscopy were applied to detect extracellular matrix (ECM) alterations and the expression levels of core pyroptosis markers including NOD-like receptor family pyrin domain-containing protein 3 (NLRP3), caspase-1 and N-terminal gasdermin D (GSDMD-N).

Transcriptomic results revealed that inflammatory response, immune regulation, and pyroptosis-related pathways were significantly enriched in myopic scleral tissues, accompanied by synchronous activation of inflammasome signaling. In vitro inflammatory intervention downregulated the expression of type Ⅰ collagen and upregulated matrix metalloproteinase-2 (MMP-2), suggesting aggravated ECM degradation. The levels of interleukin-1β (IL-1β), interleukin-18 (IL-18), cell membrane permeability, as well as NLRP3, caspase-1, and GSDMD-N were obviously increased in activated fibroblasts. Immunofluorescence and ultrastructural observations further confirmed gasdermin protein-mediated cell membrane damage and typical pyroptotic morphological changes.

In vivo animal experiments and in vitro cellular studies collectively verify that the activation of inflammasome-caspase-1-GSDMD signaling axis is involved in myopia-related scleral remodeling. Pyroptosis acts as a key mechanistic bridge linking inflammatory response and scleral structural weakening, which offers novel molecular targets for the intervention and suppression of myopia progression.