PEX11β controls early neural progenitor fate through regulation of peroxisomal fission and lipid metabolism.

Peroxisomes are metabolic organelles that undergo fission to maintain peroxisome number for lipid homeostasis and cellular function. The peroxisomal fission machinery is shared with mitochondria, and although mitochondrial fission regulates neural cell fate decisions during human neurogenesis, it remains unclear whether peroxisomal fission independently influences human neural development. PEX11β selectively regulates peroxisomal fission by promoting membrane deformation, elongation, and downstream fission factor recruitment. To uncouple mitochondrial and peroxisomal fission in early human neurogenesis, we generated PEX11β knockout iPSCs and tracked differentiation into neural progenitors and neural rosettes. At the cellular level, perturbing PEX11β selectively impaired peroxisomal lipid metabolism, characterized by reduced ether-linked phospholipids. At the tissue level, PEX11β deficiency altered neural rosette architecture, resulting in enlarged central lumens and expanded neural progenitor populations. This human neural model uncouples mitochondrial and peroxisomal fission and positions PEX11β as a distinct regulator of lipid metabolism and neural progenitor fate during human neurogenesis.