SETD5, a member of the protein lysine methyltransferase family, is best known for methylating histone H3 on lysine 36 (H3K36), playing roles in transcription regulation, euchromatin formation, and RNA elongation and splicing. It is involved in chromatin modification pathways, which are crucial for normal physiological processes, especially in brain development [1,3].

SETD5 has been identified as a key factor in multiple disease conditions. In pancreatic ductal adenocarcinoma (PDAC), its induction is associated with resistance to MEK1/2 inhibition, and its deletion restores drug vulnerability in mouse models and patient-derived xenografts [2]. In neural cells, SETD5 haploinsufficiency leads to mitochondrial impairment, including fragmented mitochondria, reduced membrane potential, and ATP production, as seen in in vitro neural stem cells and the brains of Setd5 haploinsufficiency mouse models [4]. In hepatocellular carcinoma (HCC), SETD5 depletion decreased cell proliferation, invasion, and induced cell death, and inhibited tumor growth in xenograft mouse models [5]. In breast cancer stem-like cells, down-regulation of SETD5 significantly decreased stem-like properties and glycolysis in vitro and in vivo [6]. In retinal development, Setd5, but not Setd2, is essential for sustaining retinal cell survival and proliferation in mouse retinal explant cultures [7].

In conclusion, SETD5 is crucial for normal physiological processes, especially in neural development and metabolism-related functions. Studies using KO/CKO mouse models have revealed its significant roles in various diseases such as neurodevelopmental disorders, pancreatic cancer, liver cancer, breast cancer, and in maintaining retinal cell survival. These findings provide potential therapeutic targets for related diseases.