Metabolic Checkpoints in IgA Nephropathy: From Pathogenesis to Precision Medicine

Immunoglobulin A nephropathy (IgAN), the most prevalent primary glomerulopathy globally, exhibits intricate pathomechanisms and significant clinical heterogeneity, with up to 50% of patients progressing to kidney failure within 20 years. Contemporary management of IgAN combines causal therapy against pathogenic galactose-deficient immunoglobulin A1, including enteric budesonide with symptom-oriented interventions via renin-angiotensin system inhibitors to mitigate hypertension, glomerular hyperfiltration, proteinuria, and cardiovascular sequelae. Nevertheless, suboptimal treatment efficacy observed in 20-30% of patients with IgAN implies the existence of additional pathogenic mechanisms beyond current therapeutic targeting. Emerging evidence underscores the pivotal role of metabolic checkpoints-central regulatory hubs governing glucose, lipid, amino acid, and mitochondrial networks-in driving a self-perpetuating pathogenic loop linking metabolic reprogramming and immune dysregulation in IgAN. Mechanistically, hypoxia-driven stabilization of hypoxia-inducible factor 1-alpha hyperactivates aerobic glycolysis, fueling T helper 17 cell/T regulatory cell imbalance and mesangial proliferative injury. Peroxisome proliferator-activated receptor dysfunction exacerbates lipotoxic damage and fibrosis. Indoleamine 2,3-dioxygenase 1- and arginase 1-mediated amino acid metabolic disturbances disrupt immune homeostasis. Meanwhile, mitochondrial oxidative stress, coupled with maladaptive unfolded protein response, propagates tubular injury through reactive oxygen species-mediated NOD-like receptor family pyrin domain containing 3 inflammasome activation and epigenetic dysregulation. Interventions targeting metabolic checkpoints, including sodium-glucose cotransporter 2 inhibitors, mechanistic target of rapamycin inhibitors and peroxisome proliferator-activated receptor-γ agonists demonstrate promising renoprotective effects in IgAN preclinical models and early-phase trials, heralding the era of dual metabolic-immune precision therapeutics. However, it is critical to emphasize that these emerging strategies currently constitute a hypothesis-generating framework and must be validated in future large-scale, randomized controlled trials with adequate power and follow-up before clinical application. Future research should integrate multi-omics and single-cell analysis to delineate metabolic heterogeneity and develop renal-targeted nanodelivery systems for endotype-based precision medicine. This paradigm shift will guide IgAN mechanism exploration and management, transitioning from conventional immunosuppression to metabolic-immune synergy regulation.