Mechanistic studies demonstrate that ferroptotic stress in HD is exacerbated by impaired mitochondrial bioenergetics, increased labile iron originating from dysfunctional iron–sulfur cluster biogenesis, and dysregulation of lipid-metabolizing enzymes such as acyl-CoA synthetase long-chain family member 4 (ACSL4) and arachidonate 5-lipoxygenase (ALOX5), which promote peroxidation of PUFA-containing phospholipids. This evidence concerns the gene ACSL4 and Huntington disease.