Metabolic reprogramming mechanisms of renal fibrosis in IgG4-related diseases:From immune dysregulation to the imbalance of energy homeostasisOA

Renal fibrosis in immunoglobulin G4(IgG4)-related disease(IgG4-RD)results from a complex interaction between dysregulated immune responses and altered cellular metabolism.Characteristic pathological hallmarks include tubulointerstitial fibrosis,dense plasma cell infiltrates,and tubular atrophy,which are frequently associated with prominent aggregates of IgG4-positive plasma cells.Metabolic reprogramming plays a pivotal role in the pro-gression of renal fibrosis.This process initiates mitochondrial dysfunction,which drives a shift toward enhanced glycolysis and suppressed fatty acid oxidation within immune cells.These metabolic alterations critically promote the acquisition of profibrotic phenotypes in key immune populations,notably M2 macrophages and T follicular helper cells.Furthermore,metabolic reprogramming directly modulates central signalling pathways integral to fibrogenesis,including the transforming growth factor-β/mothers against decapentaplegic homologue 3(TGFβ/SMAD3)and adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor γ(AMPK-PPARγ)axes.Consequently,it disrupts cellular energy homeostasis and exacerbates oxidative stress.This cascade establishes a self-perpetuating vicious cycle,inextricably linking dysregulated metabolism,aberrant im-mune responses,and the progression of fibrosis.Key signalling pathways(such as the TGF-β/SMAD3 and AMPK-PPAR axes)regulate the imbalance of energy metabolism and oxidative stress,forming a vicious cycle of metabolism-immunity-fibrosis.Adenosine triphosphate-binding cassette transporters(ABC transporters)are involved in the remodelling of the fibrotic microenvironment and therapeutic resistance through metabolite transport and drug efflux.Metabolomics and integrated multiomics technologies(such as AI-driven metabolic network modelling)provide new directions for precise diagnosis and targeted intervention.This review system-atically analyses the metabolic regulatory network of renal fibrosis in IgG4-RD,emphasizes the potential of tar-geting metabolic nodes(such as restoring nicotinamide adenine dinucleotide(NAD+)levels and inhibiting glycolysis)to reverse fibrosis,and looks ahead to metabolomics-driven personalized treatment strategies.