# STING deficiency alleviates scar formation after glaucoma filtration surgery by suppressing p38 MAPK-induced inflammation in mice

## TL;DR

STING deficiency reduces scarring after glaucoma surgery in mice by lowering inflammation and fibrosis via the p38 MAPK pathway.

## Contribution

This study reveals a novel role of STING in post-surgical fibrosis and identifies the STING/p38 axis as a potential therapeutic target.

## Key findings

- STING deficiency in mice prolonged bleb survival and reduced collagen deposition after glaucoma surgery.
- STING inhibition suppressed p38 MAPK signaling and decreased pro-inflammatory and fibrogenic markers.
- Findings were corroborated in human fibroblasts treated with STING silencing or H151.

## Abstract

Glaucoma filtration surgery (GFS) often fails because of excessive scar formation driven by inflammation and fibroblast activation. Although the stimulator of interferon genes (STING) pathway is involved in inflammatory responses, its role in post-surgical fibrosis remains unclear.

A mouse GFS model was established in wild-type (WT) and STING-knockout (STING-KO) animals. A parallel cohort of WT mice received a single intraoperative subconjunctival injection of the STING inhibitor H151. Bleb survival, intraocular pressure, histopathology, collagen deposition, and inflammatory/fibrotic markers were evaluated for 28 days. RNA sequencing, Western blotting, and ELISA were employed to profile the p38/MAPK axis. Primary human Tenon’s capsule fibroblasts were treated with angiotensin II in the presence or absence of STING silencing or H151 to corroborate mechanisms in vitro.

STING expression was markedly up-regulated in fibroblasts within human and mice post-GFS tissues. STING-KO mice exhibited prolonged bleb survival together with reduced collagen deposition and fibroblast activation. RNA-sequencing revealed that STING deletion significantly altered the p38 mitogen-activated protein kinase (MAPK) pathway. Mechanistically, STING deficiency suppressed p38 MAPK phosphorylation, leading to decreased levels of the pro-inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor-α, IL-18, and IL-1β, as well as the fibrogenic factors α-SMA, collagen I, fibronectin, connective tissue growth factor, and collagen type III alpha 1 at the surgical sites. Consistently, the selective STING inhibitor H151 recapitulated these effects by suppressing p38 MAPK signaling and markedly reducing fibrotic scarring.

STING deficiency alleviates scar formation after GFS by suppressing p38 MAPK pathway. Targeting STING/p38 axis may improve surgical outcomes by modulating the balance between inflammation and tissue repair.

The online version contains supplementary material available at 10.1186/s40662-026-00475-3.