# MUC20 alleviates kidney fibrosis by modulating pyroptosis through the MET/RAS/STING axis

## TL;DR

MUC20 protects the kidney by preventing harmful cell death and fibrosis through a specific signaling pathway involving RAS and STING.

## Contribution

This study reveals MUC20's novel role in kidney fibrosis by modulating pyroptosis via the MET/RAS/STING axis.

## Key findings

- MUC20 deficiency worsens kidney fibrosis and increases pyroptosis in tubular cells.
- MUC20 interacts with MET to activate RAS, inhibiting cGAS-STING pathway activation.
- STING activation leads to lysosomal disruption and NLRP3 inflammasome-mediated pyroptosis.

## Abstract

Rationale: Mucins are epithelial transmembrane glycoproteins involved in inflammation and kidney dysfunction, yet the role of the transmembrane mucin MUC20 in renal injury and fibrosis remains unclear. This study aimed to define the functional significance and underlying mechanisms of MUC20 in kidney fibrosis.

Methods:
Muc20-deficient mice and tubular epithelial cell models were used to evaluate renal fibrosis and pyroptosis in induced kidney injury. Molecular and biochemical approaches were applied to assess protein interactions, RAS activation, 2′3′-cGAMP production, cGAS-STING signaling, lysosomal integrity, potassium efflux, and NLRP3 inflammasome activation.

Results: Loss of MUC20 significantly exacerbated renal fibrosis and increased pyroptosis in tubular epithelial cells. Mechanistically, MUC20 interacted with MET to promote RAS activation. MUC20 deficiency decreased GTP-bound RAS levels, leading to increased 2′3′-cGAMP production and activation of the cGAS-STING pathway. STING activation induced lysosomal membrane permeabilization, potassium efflux, and subsequent NLRP3 inflammasome-mediated pyroptosis.

Conclusions: MUC20 acts as a key protective regulator in kidney by restraining RAS-cGAS-STING-NLRP3-driven pyroptosis and fibrotic progression. Targeting MUC20-related signaling pathways may offer therapeutic potential for kidney fibrosis and chronic kidney disease.