HADHB encodes the beta subunit of the mitochondrial trifunctional protein (MTP) complex, which catalyzes the final three reactions of the mitochondrial beta-oxidation pathway for long-chain fatty acid metabolism 1. The MTP complex is heterotetrameric, with HADHB providing 3-ketoacyl-CoA thiolase activity while partnering with HADHA for complete fatty acid oxidation 2. This enzymatic function is essential for energy production, particularly during fasting states when fatty acid oxidation becomes the primary metabolic pathway 1. HADHB mutations cause MTP deficiency, an autosomal recessive disorder presenting with three distinct phenotypes: early-onset cardiomyopathy with high mortality, intermediate forms with hypoketotic hypoglycemia, and late-onset sensorimotor neuropathy with episodic rhabdomyolysis 1. The protein has been identified as a critical component in severe childhood cardiomyopathies, where genetic variants contribute to metabolic dysfunction 3. HADHB expression is regulated by transcription factors like PPARγ through NPR-C signaling pathways 4 and can be epigenetically silenced through DNA methylation mechanisms involving TET2 5. Clinically, reduced HADHB expression correlates with poor prognosis in colorectal cancer and contributes to various metabolic diseases 56.