KLHL6 (kelch like family member 6) functions as an E3 ubiquitin ligase that regulates multiple cellular processes through targeted protein degradation. As part of the Cul3-RING ubiquitin ligase complex, KLHL6 targets specific substrates for proteasomal degradation 12. In B-cells, KLHL6 regulates the B-cell receptor complex by targeting CD79B for degradation, thereby controlling surface BCR expression in germinal center B cells 3. KLHL6 also degrades Roquin2, an mRNA decay factor involved in NF-κB pathway regulation 1. In T-cell immunity, KLHL6 prevents exhaustion by promoting TOX degradation and maintains mitochondrial fitness by regulating the PGAM5-Drp1 axis 4. KLHL6 functions as a tumor suppressor in diffuse large B-cell lymphoma (DLBCL), where recurrent mutations disrupt its interaction with cullin3, leading to loss of function 12. Loss of KLHL6 activity promotes chemoresistance in DLBCL and contributes to NOTCH2 stabilization 2. Driver mutations in KLHL6 are found in multiple myeloma and autoimmune diseases, suggesting broad roles in hematologic malignancies 56. KLHL6 expression levels affect sensitivity to polatuzumab vedotin therapy in B-cell lymphomas 3.