KLHL42 (kelch like family member 42) is a substrate-specific adapter of the BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex essential for mitotic progression and microtubule dynamics. The complex mediates ubiquitination and degradation of multiple substrates including KATNA1 (p60/katanin) 1 and PPP2R5ϵ 2. KLHL42 plays critical roles in disease pathogenesis across multiple contexts. In cancer, MYC amplification induces KLHL42 transcription to promote RB1 degradation, conferring resistance to CDK4/6 inhibitors in bladder, prostate, and breast cancers 3. In systemic sclerosis, KLHL42 acts as a profibrotic ligase controlling TGF-β/SMAD2/3 signaling through PPP2R5ϵ degradation, with KLHL42 knockdown reducing fibrotic tissue production and SMAD activation in patient lung fibroblasts 2. KLHL42 also functions in cutaneous T cell lymphoma, where it is transcriptionally activated by GATA3 and promotes aggressive cell proliferation; KLHL42 silencing inhibits proliferation and promotes apoptosis 4. Additionally, miR-26a-5p targets KLHL42 to suppress renal fibrosis in diabetic nephropathy 5, and KLHL42 has been identified as a functional gene in type 2 diabetes pathology 6. These findings suggest KLHL42 inhibition represents a promising therapeutic strategy across multiple fibrotic and neoplastic diseases.