Ncoa6, also known as NRC, ASC-2, TRBP, PRIP and RAP250, is a transcriptional co-activator. It is involved in multiple biological processes such as embryonic development, metabolism, and is also associated with cancer pathogenesis [3]. Ncoa6 is a multifunctional coregulator necessary for the transcriptional activation of a wide range of target genes and may modulate chromatin structure through histone methylation [3].

Ncoa6-deficient macrophages showed markedly inhibited NLRP3 hyperactivation caused by the Nlrp3R258W gain-of-function mutation. Genetic ablation of Ncoa6 in mice substantially attenuated the severity of NLRP3-dependent diseases like folic-induced acute tubular necrosis and crystal-induced arthritis, indicating its critical role in NLRP3 inflammasome activation [1]. In pancreatic cancer, Ncoa6 knockdown suppressed cell proliferation, migration, and invasion. Also, Ncoa6 knockdown enhanced RSL3-induced ferroptosis in pancreatic cancer cells and increased their sensitivity to gemcitabine [2,4]. In pancreatic β-cells, Ncoa6 stimulates insulin secretion by modulating Nampt expression [6]. Germline depletion of Ncoa6 in mice leads to embryonic lethality and heart defects, and mutations in NCOA6 are present in some patients with idiopathic dilated cardiomyopathy (iDCM) [5].

In conclusion, Ncoa6 is a crucial transcriptional co-activator involved in diverse biological functions including immune response, cell growth and metabolism, and insulin secretion. Gene knockout mouse models have been instrumental in revealing its roles in NLRP3-dependent diseases, pancreatic cancer, pancreatic β-cell function, and heart diseases such as DCM. These findings offer potential therapeutic targets for related diseases.