FLAV-27 COUNTERACTS TRANSCRIPTIONAL DYSREGULATION AND FERROPTOSIS SUSCEPTIBILITY IN HUNTINGTON’S DISEASE MODELS BY REPROGRAMMING H3K9ME2 EPIGENETICS

Huntington's disease (HD) is a deadly neurodegenerative disorder inherited in an autosomal dominant pattern, caused by an abnormal expansion of the CAG trinucleotide repeat in the huntingtin gene. It features progressive neuronal loss and early transcriptional dysregulation. Evidence suggests that epigenetic mechanisms, especially abnormal histone modifications that impact chromatin accessibility, contribute to pathogenic gene expression changes that start before symptoms appear and play a key role in disease progression. In HD, the histone methyltransferase G9a, which adds the repressive H3K9me2 mark, leads to abnormal silencing of neuronal genes vital for synaptic function and neuroprotection, while activating harmful transcription programs. FLAV-27 is a selective G9a inhibitor that competes with SAM, penetrates the brain effectively, and has shown neuroprotective effects in AD. However, its potential in HD has not been tested. To explore this, we used models in C. elegans and Hdh+/Q111 knock-in mice to assess FLAV-27’s therapeutic effects. In C. elegans, FLAV-27 reduces huntingtin aggregates in a dose-dependent manner and improves motor function. In mice, FLAV-27 restores cognitive and motor abilities, lowers brain H3K9me2 to near-normal levels, and normalizes the expression of genes involved in glutamatergic neurotransmission, synaptic plasticity, calcium regulation, and proteostasis. It also upregulates genes protecting against ferroptosis and decreases markers of oxidative stress and neuroinflammation. Elevated H3K9me2 was confirmed in postmortem brain tissue from HD patients, confirming this epigenetic change as a potential biomarker. These results propose that G9a inhibition could offer neuroprotection in HD via epigenetic reprogramming, with clinical implications supported by detectable biomarkers.