HIBADH (3-hydroxyisobutyrate dehydrogenase) is a mitochondrial enzyme that catalyzes the oxidative degradation of valine, a branched-chain amino acid, by converting 3-hydroxyisobutyrate to methylmalonate semialdehyde 1. The enzyme localizes to the mitochondrial matrix and plays critical roles in metabolic homeostasis and cellular protection. Mechanistically, HIBADH regulates mitochondrial function and oxidative stress. In kidney pathology, HIBADH overexpression reduces crystal adhesion, suppresses apoptosis, enhances ATP production, and maintains mitochondrial membrane potential through modulation of mitochondria-involved oxidative stress 2. Additionally, a long non-coding RNA derived from the HIBADH locus (lnc-HIBADH-4) regulates the autophagy-lysosome pathway by targeting cathepsin D, affecting cellular proliferation and apoptosis dynamics 3. Clinically, HIBADH deficiency causes a novel metabolic disorder characterized by 3-hydroxyisobutyrate accumulation in urine, manageable through low-valine diet intervention 1. HIBADH dysfunction is implicated in calcium oxalate nephrolithiasis pathogenesis, where reduced expression increases kidney stone formation and tubular injury 2. Genome-wide association studies identify HIBADH as a shared genetic risk factor between kidney stone disease and sepsis 4, and emerging evidence links HIBADH alterations to suicide attempt risk through altered brain proteomics 5. Gene expression regulation involves promoter polymorphisms affecting transcriptional activity 6 and epigenetic modifications responsive to environmental exposures 7.