Insulin-like growth factor 2 reduces Huntington's disease aggregates via AKT and NF-κB signaling in huntington's disease.

BACKGROUND: Aggregation of misfolded mutant Huntingtin (mHTT) is a pathological characteristic in Huntington’s disease (HD), implying clearance of mHTT is a therapeutical direction for this neurodegenerative disorder. Based on previous studies, Insulin-like growth factor 2 (IGF2) enhances microfilament polymerization in HD models; however, the role of IGF2 against mHTT aggregates is still unclear. RESULTS: Here, we demonstrate that IGF2 expression is significantly lower in symptomatic HD patients compared to presymptomatic individuals, and IGF2 activation mechanistically enhances phosphorylation of Protein Kinase B(AKT; serine/threonine kinase), which subsequently reduces mHTT aggregates in vitro. Furthermore, IGF2 stimulates Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, promoting the secretion of mHTT within extracellular vesicles, thereby aiding cellular clearance. In vivo studies in R6/2 HD transgenic mice reveal that IGF2 administration improves motor functions and decreases mHTT levels. CONCLUSIONS: Collectively, our findings elucidate the multifaceted role of IGF2 in HD, highlighting its therapeutic potential through modulation of AKT and NF-κB signaling pathways. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-025-01452-4.