KLHL38 (kelch like family member 38) functions as a substrate adaptor protein within the Cul3-RING ubiquitin ligase complex, mediating the proteasomal degradation of specific cellular targets 1. As a component of this E3 ubiquitin ligase machinery, KLHL38 facilitates K48-linked ubiquitination and subsequent degradation of key regulatory proteins including beclin 1 (BECN1) and myocardin 12. By promoting BECN1 degradation, KLHL38 suppresses autophagy and promotes tumor progression in breast and ovarian cancers 1. In non-small cell lung cancer (NSCLC), KLHL38 upregulation activates the Akt signaling pathway through PTEN ubiquitination, enhancing cell proliferation, migration, and invasion; elevated KLHL38 levels correlate with worse clinicopathological outcomes 3. Conversely, KLHL38 is downregulated during androgen-mediated reversion of skeletal muscle atrophy, functioning as an anti-atrogene 4. In cardiac tissue, elevated KLHL38 expression facilitates cardiomyocyte apoptosis through myocardin degradation, implicating it in heart failure progression 2. KLHL38 demonstrates tissue-specific epigenetic regulation with specialized enhancer chr8 architecture in muscle 5, suggesting context-dependent functions in disease pathogenesis. These findings identify KLHL38 as a potential therapeutic target across multiple cancer types and cardiac disease.