The KCTD (potassium channel tetramerization domain-containing protein) family is conserved in various jawed vertebrates, yet its biological function is still largely unknown. Human KCTD family consists of 25 members, including KCTD1–21, TNFAIP1, KCNRG, SHKBP1, and BTBD10 (Liu et al., 2013, Teng et al., 2019). N-terminal BTB/POZ (bric-a-brac, tramtrack, and broad complex/poxvirus zinc finger) domain, the featured domain of KCTD family genes, consists of approximately 95 amino acids and mediates the oligomerization of KCTDs and the interactions with various proteins (Pinkas et al., 2017). KCTD family members have been reported to be associated with various human diseases (Angrisani et al., 2021, Teng et al., 2019). For example, KCTD3, KCTD7, KCTD13, and KCTD17 are enriched in the brain, and mutations or deletions of these proteins may lead to various neurological disorders (Alazami et al., 2015, Metz et al., 2018, Weiss et al., 2008).

Among various KCTD family members, KCTD5 is the most studied. N-terminal BTB/POZ domain of KCTD5 has been shown to mediate KCTD5’s homo/hetero-pentameric structure, instead of tetramers (Dementieva et al., 2009, Liao et al., 2023, Stogios et al., 2005). KCTD5 is involved in the regulation of protein degradation by interacting with the E3 ubiquitin ligase Cullin3 through its BTB domain (Scott et al., 2016). In the KCTD5/Cullin3 complex, KCTD5 functions as an adapter for specific substrates (Bayon et al., 2008). KCTD5 may play a role in regulating protein trafficking, for its C-terminal domain was shown to interact with the Golgi protein GRASP55 (Dementieva et al., 2009, Gandhi et al., 2006).

Recent study described that in striatal neurons, KCTD5 may act as an important regulatory factor in the synthesis of cyclic adenosine monophosphate (cAMP), which is catalyzed by adenylyl cyclases (AC). It modulates Zip14-mediated allosteric AC regulation by mediating the ubiquitination of Zip14 and subsequent proteasome degradation. Besides Zip14, KCTD5 can also modulate the activity of G protein-coupled receptors (GPCRs) signal and Gβγ subunit by mediating the ubiquitination of Gβγ and subsequent proteasome degradation (Brockmann et al., 2017, Muntean et al., 2022).

Furthermore, increasing evidence suggests that KCTD5 may play a role in cancer development and could be a potential therapeutic target in cancer treatment (Canales et al., 2020, Shi et al., 2022). KCTD5 can affect Rac1 activity and Ca2+ signaling, playing a negative regulatory role in melanoma and breast cancer cell migration (Canales et al., 2020); high expression of KCTD5 is also associated with lymph node metastasis (Shi et al., 2022).

Despite the increasing research on KCTD5’s function at the molecular level, KCTD5’ physiological and pathological roles in animals are still largely unknown. To this end, we generated the Kctd5 knockout (KO) mice and recorded the phenotype of mice from embryos to adults. We found that Kctd5-/- mice exhibited early embryonic lethality, yet Kctd5+/- mice can be born normally. Compared to wild-type mice, Kctd5+/- mice have a shorter lifespan and show spleen enlargement, abnormal blood cell counts, and metabolic disorders during growth and development. Experimental validation revealed that KCTD5 may affect the PPAR signaling pathway and the expression of Apo family genes, thereby influencing the metabolic system. Taken together, these findings demonstrate that KCTD5 plays a previously unrecognized role in the regulation of lipid metabolism. The molecules and animal phenotype identified in this study will provide clues for further investigation into the functions of KCTD5 in various biological processes.