Peroxisomal beta-oxidation (perFAO)

Peroxisomal beta-oxidation is a critical metabolic pathway located within peroxisomes that is responsible for the catabolism of lipid species that cannot be efficiently processed by mitochondria. This system primarily targets very-long-chain fatty acids (VLCFAs, C22 and longer), branched-chain fatty acids (such as phytanic and pristanic acids), and bile acid intermediates [1, 8]. The pathway proceeds through four recurring enzymatic steps—oxidation (catalyzed by Acyl-CoA oxidase), hydration, dehydrogenation (catalyzed by D-bifunctional protein), and thiolysis—eventually shortening the carbon chains to products like octanoyl-CoA or acetyl-CoA, which are then shuttled to the mitochondria for complete oxidation [3, 10]. Clinical significance of the pathway is highlighted by severe genetic disorders such as X-linked adrenoleukodystrophy (X-ALD) and Zellweger syndrome, where defects in peroxisomal transport or assembly lead to the toxic accumulation of VLCFAs in the central nervous system and adrenal glands [8, 14]. From a therapeutic perspective, the pathway is regulated by the nuclear receptor PPAR-alpha, and agonists like fibrates are used to induce peroxisomal activity to treat hyperlipidemia and hepatic steatosis [3, 5]. Conversely, certain enzymes within this pathway, such as DECR2, are being investigated as novel targets in oncology (particularly prostate cancer) to disrupt the lipid-dependent growth of treatment-resistant tumors [12].

Other names

Peroxisomal fatty acid beta-oxidationPeroxisomal fatty acid oxidationPeroxisomal β-oxidationperFAO

Induction of peroxisomal beta-oxidation via activation of PPAR-alpha transcription factors which upregulates the expression of ACOX1, EHHADH, and ACAA1 genes; selective inhibition of specific pathway enzymes (e.g., DECR2) to starve cancer cells of lipid substrates [3, 12].