Targeting Klotho Signaling for Neuroprotection in Huntington’s Disease: A Comprehensive Review

Abstract

HD is a hereditary neurodegenerative disease caused by the amplification of the CAG trinucleotide repeat in the HTT gene, leading to a Mutant Huntingtin (mHTT) protein that dysregulates transcription, promotes protein aggregation, induces neuroinflammation, and impairs mitochondrial function. Motor dysfunction, cognitive decline, and mental disorders are manifestations of these biochemical abnormalities. Effective disease-modifying treatments are still limited, even with recent improvements. This review investigates the increasing relevance of Klotho, an anti-aging protein with neuroprotective, antioxidant, and anti-inflammatory characteristics, as a possible therapeutic target in Huntington disease. We did a comprehensive literature search across PubMed, Scopus, and Web of Science databases. Klotho's molecular functions in neural protection, energy metabolism, oxidative stress reduction, and anti-inflammatory signalling were investigated in the context of HD pathogenesis. Klotho appears to influence critical neurodegenerative processes involved in HD. It inhibits NF-κB and NLRP3 inflammasome activity, stimulates antioxidant enzyme expression (SOD, catalase), promotes GluN2B-NMDA receptor-mediated synaptic plasticity, and increases astrocytic aerobic glycolysis via FGFR1-ERK signaling. These functions may mitigate mHTT- induced neuronal damage. Pharmacologic treatments (e.g., PPAR-γ agonists), vitamin D, and lifestyle interventions can all modulate klotho expression. Klotho exhibits neuroprotective effects in Huntington’s disease by reducing NF-κB/NLRP3- mediated inflammation, strengthening antioxidant defenses, promoting GluN2B-NMDA– dependent synaptic plasticity, and improving astrocytic metabolic support via FGFR1–ERK signaling. One intriguing treatment approach for mutant huntingtin-induced neurotoxicity is the modification of klotho expression. Klotho is a promising neurochemical modulator with disease-modifying properties in HD. Its multifunctional protective activities are consistent with important pathological markers of HD, necessitating more preclinical and clinical studies to confirm its translational value.