Hibch, encoding 3-hydroxyisobutyryl-coenzyme A (CoA) hydrolase, is an enzyme implicated in a critical step of valine catabolism [1]. This pathway is essential for normal metabolism, and the enzyme's function is crucial for maintaining metabolic homeostasis. Genetic models, such as gene knockout (KO) or conditional knockout (CKO) mouse models, could potentially be valuable in further elucidating its function.

Pathogenic variants in the HIBCH gene lead to HIBCH deficiency, a rare mitochondrial disorder of valine metabolism. Patients often present with movement disorders, which are a hallmark of the disease. These can include permanent or paroxysmal dystonia, chorea, parkinsonism, athetosis, myoclonus, tremors, and abnormal eye movements. Other symptoms may involve motor delay, hypotonia, ataxia, seizures, poor feeding, and organic aciduria. Brain imaging often shows signal abnormalities in the deep gray matter, particularly the globus pallidi, and cerebral peduncles [1,2,5,6].

In colorectal cancer, high HIBCH expression is linked to poor survival, increased cell growth, resistant apoptosis, and decreased autophagy, with its functions depending on mitochondrial localization. A novel inhibitor SBF-1 targeting HIBCH mitochondrial localization shows antitumor effects both in vitro and in vivo and can enhance the efficacy of anti-VEGF therapy [3]. Additionally, in fatty liver disease, the hepatic valine/3-hydroxyisobutyrate (3-HIB) pathway regulated by HIBCH is implicated, with HIBCH overexpression increasing 3-HIB release and FA uptake, and knockdown increasing cellular respiration [4].

In summary, Hibch is essential for valine catabolism and metabolic homeostasis. Studies of HIBCH deficiency, often through human patient cases as no KO/CKO mouse model details were in the provided references, have revealed its importance in neurological function and disease, as well as its role in colorectal cancer and fatty liver disease. Understanding Hibch's function provides insights into these disease mechanisms and potential therapeutic targets.