KLHL25 (Kelch-like family member 25) is a substrate adapter protein for the CUL3-RING (BCR) E3 ubiquitin ligase complex that regulates translation homeostasis and lipid metabolism. As a component of the BCR(KLHL25) complex, KLHL25 mediates ubiquitination and degradation of hypophosphorylated EIF4EBP1 (4E-BP1), which serves as a homeostatic mechanism to maintain translation when eIF4E levels are low 1. The complex selectively targets only hypophosphorylated 4E-BP1, sparing the hyperphosphorylated or eIF4E-bound forms. KLHL25 also regulates lipid synthesis by promoting CUL3-mediated ACLY ubiquitination and degradation 2, thereby inhibiting fatty acid synthesis and promoting fatty acid oxidation. This metabolic reprogramming is critical for iTreg differentiation, where TGFβ1 signaling activates KLHL25 transcription through JNK-mediated histone phosphorylation, while IL-6 suppresses this pathway to favor Th17 differentiation 3. In cancer contexts, reduced CUL3 expression correlates with elevated ACLY and poor prognosis in lung cancer, suggesting KLHL25-containing complexes function as tumor suppressors 2. KLHL25 variants have been identified in diverse conditions including glioma prognosis 4, asthma pathology 5, and tick-borne encephalitis severity 6, indicating broader roles in disease susceptibility.