Serpina3c, a murine gene belonging to the serine protease inhibitor (Serpin) family, with its human homologue being SerpinA3, plays significant roles in multiple physiological and pathological processes. It is involved in insulin secretion and adipogenesis, and has been linked to pathways such as the Cathepsin G/Integrin/AKT, Wnt/β -catenin-PPARγ, and JNK-related pathways. Genetic models, especially knockout (KO) mouse models, have been crucial in understanding its functions [5].

Serpina3c deficiency in KO mice leads to a series of metabolic and pathological changes. In adipose tissue, it causes more severe obesity, lower metabolic rates, glucose intolerance, and insulin insensitivity, associated with increased inflammation and apoptosis. This is due to the activation of the Cathepsin G-mediated turnover of α5/β1 Integrin protein, disrupting the Integrin/AKT pathway [1].

In the liver, Serpina3c deficiency exacerbates non-alcoholic fatty liver disease (NAFLD), promoting necroptosis via the β-catenin/Foxo1/TLR4 signaling pathway [2]. Serpina3c -/- mice also exhibit lower body weight and white adipose tissue weight, along with increased serum and hepatic triglyceride levels without changes in glucose metabolism, suggesting an impaired adipocyte differentiation through the up-regulation of Wnt/β-catenin and down-regulation of PPARγ [3].

In the heart, Serpina3c deficiency aggravates myocardial infarction (MI) fibrosis and increases the proliferation of cardiac fibroblasts by enhancing glycolysis-related genes, with a key enzyme ENO1 being most significantly increased [4].

In conclusion, Serpina3c is essential for maintaining normal metabolic functions and tissue homeostasis. The use of Serpina3c KO mouse models has revealed its roles in diseases such as obesity, NAFLD, and heart failure, highlighting its potential as a therapeutic target for these metabolic and cardiovascular diseases.