Dgkh, coding for the eta (η) isoform of diacylglycerol kinase, is involved in the phosphoinositol pathway [4]. It may have a role in late developmental stages as its expression increases during mouse brain development [4].

In hepatocellular carcinoma (HCC), DGKH is elevated in tumor tissues. Functional assays in DGKH-manipulated HCC cell lines showed that DGKH augmented aggressive features like cancer stemness, therapy resistance, and metastasis. Mechanistically, it promotes mTOR signaling by producing phosphatidic acid, and in an immunocompetent mouse model, cotreatment with sorafenib and liver-directed AAV8-mediated Dgkh depletion reduced tumor burden and related features [1].

In bipolar disorder (BD), DGKH is a replicated risk gene. In a study, the risk haplotype of DGKH was associated with increased amygdala volume in BD patients. Also, the A allele of DGKH (rs9525580) in Japanese healthy volunteers was associated with higher scores of openness to experience, a premorbid personality trait of BD [3,5].

In addition, high glucose in hippocampal neurons can inhibit the demethylation modification of Dgkh by ALKBH5, leading to down-regulation of Dgkh, tau hyperphosphorylation, and potentially diabetic cognitive dysfunction. Overexpression of Dgkh reversed tau hyperphosphorylation in in-vitro and in-vivo models [2].

In conclusion, Dgkh is involved in multiple biological processes and disease conditions. Its role in promoting aggressive features in HCC via mTOR signaling, its association with BD in terms of amygdala volume and personality traits, and its connection to tau hyperphosphorylation in diabetic cognitive dysfunction highlight its importance. Studies on Dgkh, especially those using functional manipulation models, contribute to understanding the mechanisms of these diseases and may offer potential therapeutic targets.