Itih3, also known as inter-trypsin inhibitor heavy chain 3, has been implicated in multiple biological processes. It is involved in pathways related to metabolism, apoptosis, and extracellular matrix stabilization. It has overall importance in understanding various physiological and pathological conditions, and genetic models such as mouse models are valuable for studying its functions [1,2,3].

In a NAFLD context, Itih3 has been shown to protect against hepatic steatosis. Overexpression of hepatic Itih3 in animal models lowered liver triglyceride and lipid droplet accumulation, while knockdown in mice increased liver triglycerides in two independent NAFLD models. Mechanistically, Itih3 reduces mitochondrial respiration, downregulates de novo lipogenesis, and increases STAT1 signaling and Stat3 expression, all of which protect against NAFLD/NASH [1]. In ovarian carcinoma, downregulation of Itih3 contributes to cisplatin-based chemotherapy resistance via the Bcl-2 mediated anti-apoptosis signaling pathway. Construction of Itih3 RNA interference ovarian cancer cell lines demonstrated increased resistance to cisplatin and changes in anti-and pro-apoptotic protein expression levels [2].

In conclusion, Itih3 plays crucial roles in metabolic regulation, as seen in the context of NAFLD, and in chemosensitivity, as in ovarian carcinoma. The use of gene knockout or knockdown models in mice has been instrumental in revealing these functions, providing potential insights for biomarker discovery and therapeutic development in these disease areas.

References:

1. Talari, Noble Kumar, Mattam, Ushodaya, Kaminska, Dorota, Pihlajamäki, Jussi, Chella Krishnan, Karthickeyan. 2024. Hepatokine ITIH3 protects against hepatic steatosis by downregulating mitochondrial bioenergetics and de novo lipogenesis. In iScience, 27, 109709. doi:10.1016/j.isci.2024.109709. https://pubmed.ncbi.nlm.nih.gov/38689636/

2. Liu, Yingzhao, Shi, Lijun, Yuan, Cunzhong, Yao, Desheng, Wang, Qi. 2022. Downregulation of ITIH3 contributes to cisplatin-based chemotherapy resistance in ovarian carcinoma via the Bcl-2 mediated anti-apoptosis signaling pathway. In Oncology letters, 25, 61. doi:10.3892/ol.2022.13646. https://pubmed.ncbi.nlm.nih.gov/36644154/

3. Miyake, Yoshihiro, Tanaka, Keiko, Arakawa, Masashi. 2018. ITIH3 and ITIH4 polymorphisms and depressive symptoms during pregnancy in Japan: the Kyushu Okinawa Maternal and Child Health Study. In Journal of neural transmission (Vienna, Austria : 1996), 125, 1503-1509. doi:10.1007/s00702-018-1905-1. https://pubmed.ncbi.nlm.nih.gov/29992445/