Hmgcs2, also known as 3-hydroxy-3-methylglutaryl-CoA synthase 2, is the rate-limiting enzyme for ketone body synthesis [8]. It is involved in the ketogenesis pathway, which is crucial for energy metabolism, especially under conditions of carbohydrate restriction or increased fatty acid oxidation [1,5,7,9]. Genetic models such as gene knockout (KO) and conditional knockout (CKO) mouse models are valuable tools for studying its functions.

In NAFLD mouse models, Hmgcs2-mediated ketogenesis was found to modulate hepatic lipid regulation. Mice lacking Hmgcs2 developed spontaneous fatty liver phenotype during postnatal development, which could be rescued by a low-fat diet. Hmgcs2 heterozygous adult mice were more susceptible to diet-induced NAFLD, while HMGCS2 overexpression in NAFLD mice improved hepatosteatosis and glucose homeostasis [1]. In the context of chronic kidney disease, downregulation of LONP1, a mitochondrial protease, led to mitochondrial accumulation of HMGCS2, disrupting mitochondrial function and accelerating CKD progression [2]. In septic mouse models, silencing of Hmgcs2 accelerated septic myocardial injury, while Hmgcs2 attenuated inflammation and apoptosis, and promoted M2 macrophage polarization through the Src-dependent activation of the PI3K/Akt pathway [3]. In pancreatic ductal adenocarcinoma, HMGCS2 was overexpressed in gemcitabine-resistant tumors, and BET inhibitor-mediated decrease of HMGCS2 sensitized the tumors to gemcitabine [4]. Tacrolimus-induced decrease of HMGCS2 in mouse liver led to lipid deposition, and restoration of HMGCS2-mediated ketogenesis alleviated this disorder [5]. In diabetic nephropathy, notoginsenoside Fc ameliorated glomerular endothelial cells pyroptosis and mitochondrial dysfunction, and this effect was associated with the suppression of HMGCS2 [6]. In clear cell renal cell carcinoma, upregulation of HMGCS2 increased the expression of key tumor suppressor proteins, inhibited cell proliferation, and promoted apoptosis [8].

In conclusion, Hmgcs2-mediated ketogenesis plays a significant role in multiple biological processes and disease conditions. Model-based research, especially KO/CKO mouse models, has revealed its importance in diseases such as NAFLD, chronic kidney disease, sepsis-induced myocardial injury, pancreatic cancer, tacrolimus-induced hepatic lipid metabolism disorder, diabetic nephropathy, and clear cell renal cell carcinoma. These findings provide insights into potential therapeutic strategies targeting Hmgcs2 for the prevention and treatment of these diseases.