Inhibition of cGAS-STING signaling pathway alleviates high glucose-induced mesothelial-mesenchymal transition in human peritoneal mesothelial cell line HMrSV5

TL;DR

Blocking the cGAS-STING pathway reduces high glucose-induced changes in peritoneal cells linked to fibrosis.

Contribution

Demonstrates that inhibiting cGAS-STING signaling can alleviate mesothelial-mesenchymal transition in peritoneal cells.

Findings

High glucose increases cGAS-STING pathway activation in HMrSV5 cells.

Inhibiting cGAS-STING reduces MMT markers and cell invasion.

Suppression of the pathway lowers pro-inflammatory cytokine levels.

Abstract

The mesothelial-mesenchymal transition (MMT) of peritoneal mesothelial cells is a critical factor contributing to the progression of peritoneal fibrosis. This study aimed to explore the effect of cGAS-STING signaling pathway on the MMT process in peritoneal mesothelial cells. The expressions of cGAS, STING, α-SMA, and Vimentin in HMrSV5 cells treated with high glucose were analyzed using WB. Subsequently, si-cGAS and the cGAS inhibitor RU.521 were employed to intervene in HMrSV5 cells. qPCR was utilized to evaluate the expression levels of genes involved in the cGAS-STING signaling pathway (cGAS, STING, IRF3, TBK1) and MMT-related genes (E-cadherin, Vimentin, α-SMA, TGF-β1). The protein expressions of the cGAS-STING signaling pathway and MMT-related proteins were detected by WB. The invasive capacity of cells in each cell was assessed using a Transwell assay, and the levels of pro-inflammatory cytokines (IL-6, TNF-α) in the supernatants of each cell were measured by ELISA. In the present study, we found that the expressions of cGAS, p-STING/STING, p-IRF3/IRF3, and p-TBK1/TBK1 proteins were significantly upregulated in HG-treated HMrSV5 cells. Furthermore, the activation of the cGAS-STING signaling pathway could be effectively suppressed in HMrSV5 cells transfected with si-cGAS or treated with RU.521. Additionally, treatment with si-cGAS or RU.521 not only attenuated the invasive capacity of HMrSV5 cells but also decreased the levels of pro-inflammatory cytokines and inhibited the expression of MMT-related markers. Suppression of the cGAS-STING signaling pathway mitigates HG-induced MMT in the human peritoneal mesothelial cell line HMrSV5.

The online version contains supplementary material available at 10.1007/s11626-025-01107-1.

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