Heart failure remains a major global health burden, driven largely by pathological cardiac hypertrophy. Mitochondrial dysfunction, particularly impaired mitochondrial complex I activity, is central to the disease progression, yet its regulatory mechanisms are poorly understood. Cross-species transcriptomic screening and UK Biobank analyses identified SBK2 (Src homology 3 domain-binding kinase 2) as a conserved, cardiac-enriched kinase potentially linked to heart failure risk. We hypothesized that SBK2 regulates cardiac hypertrophy by modulating mitochondrial complex I function.