# Molecular, Metabolic and Inflammatory Patterns Involved in Pathogenesis of Anderson-Fabry Disease

## TL;DR

This paper explores the molecular and inflammatory processes in Anderson-Fabry disease to identify new treatment strategies.

## Contribution

The study highlights the role of metaflammation in Anderson-Fabry disease and suggests new therapeutic approaches beyond enzyme replacement.

## Key findings

- Gb3 accumulation disrupts autophagy and mitochondrial function, causing oxidative stress.
- Innate immune activation via TLR4/NF-κB leads to inflammation and endothelial dysfunction.
- Metaflammation links lysosomal dysfunction to chronic inflammation and fibrosis.

## Abstract

Anderson–Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, resulting in deficient α-galactosidase A activity and progressive accumulation of globotriaosylceramide (Gb3) and its derivative lyso-Gb3 within lysosomes. Beyond substrate storage, FD involves a complex interplay of molecular, metabolic, and inflammatory disturbances that collectively drive multisystemic damage. It seems that Gb3 accumulation impairs autophagic flux, promotes mitochondrial dysfunction, and triggers endoplasmic reticulum stress, leading to oxidative imbalance and bioenergetic failure. Concurrently, activation of innate immune pathways, particularly the TLR4/NF-κB axis, induces pro-inflammatory cytokine release and endothelial dysfunction, while complement activation and adaptive immune responses contribute to chronic inflammation and fibrosis. These mechanisms define a sustained state of “metaflammation,” linking lysosomal dysfunction to systemic inflammation. Understanding this molecular cross-talk provides a rationale for identifying novel biomarkers and designing therapies that go beyond enzymatic correction, including chaperone therapy, substrate reduction, and gene-based or anti-inflammatory approaches. A deeper comprehension of these interconnected patterns may guide the development of precision medicine strategies aimed at improving long-term outcomes in Fabry disease.