Upregulation of Trx alleviated high-glucose-induced Müller cell pyroptosis through ASK-1/Cav-1-mediated endoplasmic reticulum stress and autophagy.

High glucose treatment increased expression of ERS- and pyroptosis-related genes in Müller cells.

• In vivo and in vitro high glucose conditions led to increased expression of retinal inflammatory factors
• High glucose induced morphological damage in retinal Müller cells
• High glucose triggered cell pyroptosis in Müller cells
• ERS-related and pyroptosis-related gene expression were both upregulated following high-glucose treatment

Trx overexpression reversed high-glucose-induced increases in ERS- and pyroptosis-related gene expression.

• After Trx overexpression, the high-glucose-induced upregulation of ERS- and pyroptosis-related genes was reversed
• Trx is described as a small-molecule protein essential for regulating cellular function
• The reversal of these molecular changes occurred in both in vivo and in vitro models
• Serum samples from patients with diabetes, diabetic mice, and Müller cells were used to confirm these findings

Trx overexpression activated autophagy and reduced the number of TUNEL-positive cells under high-glucose conditions.

• Autophagy was activated following Trx overexpression in high-glucose-treated Müller cells
• The number of TUNEL-positive cells decreased after Trx overexpression
• These effects (autophagy activation and reduced TUNEL-positive cells) were reversed by Cav-1 inhibitor treatment
• This suggests Cav-1 is downstream of Trx in mediating autophagy and cell survival

ASK-1 and Cav-1 mediate the regulatory effects of Trx on ERS and autophagy in high-glucose-treated Müller cells.

• ASK-1 (apoptosis signal-regulating kinase 1) and Cav-1 (caveolin-1) were found to be closely associated with ERS and autophagy in this context
• Trx overexpression delayed high-glucose-induced Müller cell pyroptosis by regulating ERS and autophagy via the ASK-1/Cav-1 pathway
• Cav-1 inhibitor treatment reversed the beneficial effects of Trx overexpression on autophagy and TUNEL-positive cell counts
• The ASK-1/Cav-1 axis is identified as the mechanistic link between Trx activity and downstream cellular stress responses

High glucose induced retinal changes consistent with diabetic retinopathy progression in both in vivo and in vitro models.

• Diabetic mice and high-glucose-treated Müller cells were used as experimental models alongside serum samples from patients with diabetes
• High glucose led to increased expression of retinal inflammatory factors
• Morphological damage to retinal Müller cells was observed under high-glucose conditions
• These changes ultimately promote the progression of diabetic retinopathy