Huntingtin (HTT) is a ubiquitous protein involved in multiple cellular processes including autophagosome formation and DNA repair regulation 1. Wild-type HTT interacts with numerous cellular partners, including exonuclease 1 (Exo1) and mismatch repair protein MLH1, where it functions to suppress DNA end resection and stabilize MLH1 during DNA double-strand break repair 2. HTT also regulates palmitoylation through interactions with palmitoyl acyltransferases HIP14 and HIP14L, modulating the post-translational modification of multiple neuronal substrates 3. Huntington disease (HD) results from CAG repeat expansion in the HTT gene, producing mutant huntingtin (mHTT) with an abnormally long polyglutamine stretch 4. This polyQ expansion confers toxic functions causing protein aggregation and misfolding 4. Mechanistically, mHTT exhibits severely reduced interaction with Exo1 and MLH1, leading to MLH1 degradation, hyperactive DNA excision, DNA damage accumulation, and cGAS-STING pathway activation culminating in apoptosis 2. Additionally, the HD mutation disrupts HIP14-HTT interactions, reducing palmitoylation of HTT and other HIP14 substrates, promoting neuronal toxicity and striatal atrophy 3. Clinically, HTT lowering represents a disease-modifying strategy; the splicing modifier PTC518 achieved dose-dependent reductions in HTT mRNA (up to 60%) and protein levels (up to 35%) with favorable tolerability in healthy volunteers, supporting further clinical development 5.