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Peroxisome-derived ether lipids regulate lysosomal homeostasis through exocytosis control

ABSTRACT: Lysosomes and peroxisomes are essential for cellular homeostasis, yet how their activities are coordinated remains poorly understood. Here, we identify peroxisome-derived ether lipids as key regulators of lysosomal function. A genome-wide CRISPR/Cas9 screen in Mucolipidosis V (LYSET-deficient) cells revealed that disruption of ether lipid synthesis genes or peroxins markedly reduces lysosome accumulation and restores degradative capacity. Genetic or pharmacological inhibition of ether lipid synthesis enhanced lysosomal exocytosis through TRPML1- and SNARE-dependent pathways, promoting clearance of undigested material independently of mannose-6-phosphate trafficking. Conversely, supplementation with the ether lipid precursor hexadecylglycerol increased lysosome abundance and impaired digestion. These findings uncover a peroxisome–lysosome metabolic axis in which ether lipids act as bidirectional regulators of lysosomal number and function independent of the lysosomal master regulator TFEB. This mechanism reveals how lipid metabolism modulates lysosomal homeostasis and provides insights into potential new strategies to combat lysosomal and peroxisomal disorders.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Liang Chen

LAB HEAD: Ming Li

PROVIDER: PXD074652 | Pride | 2026-05-03

REPOSITORIES: Pride

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			Action	DRS
	107395.mzXML	Mzxml
	107395.raw	Raw
	107395_406Silac.xlsx	Xlsx
	107396.mzXML	Mzxml
	107396.raw	Raw

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