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

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 accu-mulation 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 im-pairs 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 con-tribute to chronic inflammation and fibrosis. These mechanisms define a sustained state of “met-aflammation,” linking lysosomal dysfunction to systemic inflammation. Understanding this molecular cross-talk provides a rationale for identifying novel biomarkers and designing thera-pies 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.