Hmgcr, short for 3-hydroxy-3-methylglutaryl-CoA reductase, is a key enzyme in the mevalonate pathway, which is crucial for cholesterol synthesis [3,4,5]. Cholesterol is essential for cell membrane integrity, steroid hormone synthesis, and bile acid production. Thus, Hmgcr is of great biological importance in maintaining normal physiological functions. Genetic models, such as KO/CKO mouse models, can be used to study the gene's function and its role in related biological processes and diseases.

In the context of disease, anti-Hmgcr autoantibodies are associated with a subset of immune-mediated necrotizing myopathy (IMNM), often related to statin use. These antibodies define a unique population of IMNM patients. The true incidence of anti-Hmgcr IMNM is unknown, and there is heterogeneity in phenotype and treatment response within this subgroup. Statin-naïve adults and juvenile patients may have distinct characteristics. Even with multimodal immunosuppression, patients remain prone to relapse, with younger patients having more refractory disease [1]. Additionally, Hmgcr may play a role in the interaction between ferroptosis and pyroptosis. It was found that BRCC36 deubiquitinates Hmgcr, inhibiting ferroptosis and promoting pyroptosis. Also, in hepatocellular carcinoma (HCC), Hmgcr is up-regulated, promoting the stemness and metastasis of HCC by activating the Hedgehog signaling pathway, and can be targeted by simvastatin [2,4]. Moreover, in regulatory T cells, loss of AMPK promotes the expression of Hmgcr, which is involved in the AMPK-mediated regulation of PD-1 expression via the Hmgcr/p38 MAPK/GSK3β signaling pathway, influencing antitumor immunity [3].

In conclusion, Hmgcr is vital for cholesterol synthesis through the mevalonate pathway. Model-based research, especially studies with KO/CKO mouse models (although not directly described in the given references but conceptually relevant), can further clarify its function. Its association with IMNM, as well as its roles in cell death regulation, tumor metastasis, and immune regulation, highlights its importance in multiple disease areas.