Targeting the peroxisomal FASN-ACOX2 axis to modulate energy homeostasis: therapeutic potential and challenges

Peroxisomes are increasingly recognized as active contributors to cellular thermogenesis beyond their classical oxidative role. The Nature study by Liu et al. identifies a peroxisomal FASN-ACOX2 axis in adipocytes that mediates UCP1-independent heat production through cyclic synthesis and oxidation of monomethyl branched-chain fatty acids (mmBCFAs). In adipocytes, cold exposure induces the cytoplasmic enrichment of fatty acid synthase (FASN) adjacent to peroxisomes, where it provides substrates for acyl-CoA oxidase 2 (ACOX2)-dependent oxidation. The FASN spatial relocation may couple lipogenesis with energy dissipation, raising the possibility that enzyme subcellular distribution represents a way of fine-tuned metabolic regulation. Adipocyte ACOX2 acts as the peroxisomal executor of this UCP1-independent thermogenesis cycle and a potential metabolic target linking lipid flux to systemic energy expenditure. However, the metabolic role of the FASN-ACOX2 axis outside adipose tissue, and the upstream signals that coordinate FASN redistribution with ACOX2 induction, remain to be defined. Elucidating these mechanisms could ultimately inform novel therapeutic strategies aimed at modulating peroxisomal thermogenesis to treat obesity-associated metabolic disorders.