KLHL8 (kelch like family member 8) functions as a substrate-specific adapter of the BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex. Its primary role involves mediating ubiquitination and proteasomal degradation of target proteins. KLHL8 was initially characterized as essential for ubiquitination of rapsyn, a postsynaptic protein required for nicotinic acetylcholine receptor clustering at the neuromuscular junction 1. More recently, KLHL8 has been identified as a critical regulator of ferroptosis in neuronal contexts. During ischemic stroke, KLHL8-mediated ubiquitination of GPX4 (a ferroptosis inhibitor) promotes its binding to the autophagy receptor TAX1BP1, leading to autophagic-lysosomal degradation and subsequent neuronal ferroptosis 2. Clinical evidence demonstrates that KLHL8 expression is significantly upregulated in ischemic stroke patient brain tissue and correlates with ferroptosis markers 2. KLHL8 also exhibits disease relevance in schizophrenia, where it shows gain-of-function interactions with hyperphosphorylated MAP2, nominating it as a potential therapeutic target 3. Additionally, KLHL8 variants have been associated with hepatocellular carcinoma risk 4, early-onset coronary atherosclerotic disease 5, and NAFLD fibrosis progression with sex/menopause-specific effects 6. These findings suggest KLHL8 represents a potential therapeutic target across multiple diseases involving protein quality control and ferroptosis regulation.