Itih3, also known as inter-trypsin inhibitor heavy chain 3 or inter-alpha-trypsin inhibitor heavy chain H3, is a hepatokine. It plays a role in multiple biological processes. In the liver, it is associated with regulating mitochondrial bioenergetics and de novo lipogenesis, and may be involved in extracellular matrix stabilization [1,3].

In non-alcoholic fatty liver disease (NAFLD), Itih3 has shown significant effects. Hepatic Itih3 overexpression in animal models lowered liver triglyceride and lipid droplet accumulation, while Itih3 knockdown in mice increased liver triglyceride in two independent NAFLD models. Mechanistically, Itih3 reduces mitochondrial respiration, which in turn reduces liver triglycerides via downregulated de novo lipogenesis, accompanied by increased STAT1 signaling and Stat3 expression [1]. In ovarian carcinoma, downregulation of Itih3 contributes to cisplatin-based chemotherapy resistance via the Bcl-2 mediated anti-apoptosis signaling pathway [2].

In conclusion, Itih3 has diverse functions. In NAFLD, Itih3 is inversely related to disease severity and can protect against hepatic steatosis through regulating mitochondrial function and lipogenesis. In ovarian cancer, its downregulation is linked to chemotherapy resistance. These findings from model-based research, especially in mouse models, help understand the role of Itih3 in specific disease conditions and may provide potential directions for biomarker discovery and treatment strategies.