The endo-lysosomal-lipid axis: bidirectional interactions between membrane trafficking dysfunction and lipid...

The endo-lysosomal system is a central regulator of intracellular trafficking, cargo degradation, and metabolic homeostasis. Its dynamic function is closely intertwined with lipid metabolism, forming an integrated regulatory network termed the endo-lysosomal-lipid axis. Disruption of this axis can impair endosomal maturation, lysosomal acidification, autophagic degradation, and lysosome-centered signaling pathways, resulting in defective cellular clearance and chronic inflammatory responses. Conversely, dysfunction of the endo-lysosomal system disrupts cholesterol trafficking, lipid redistribution, and macromolecular degradation, ultimately promoting secondary lipid accumulation and metabolic imbalance. In this review, we summarize the reciprocal interactions between lipid metabolism and endo-lysosomal function, with particular emphasis on membrane trafficking, lysosomal homeostasis, autophagy, membrane contact sites, and multicellular lipid clearance networks. We further discuss how these interconnected processes contribute to disease progression and highlight emerging therapeutic strategies aimed at restoring lysosomal function and lipid homeostasis. Understanding the dynamic regulation of the endo-lysosomal-lipid axis may provide new mechanistic insights into metabolic and neurodegenerative disorders and identify novel therapeutic opportunities.