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V-ATPase-Driven Lysosomal Activation Orchestrates MEK2-Induced Endothelial Reprogramming

ABSTRACT: Direct lineage reprogramming holds therapeutic promise but often depends on transcription factor overexpression, resulting in unstable phenotypes. Here, we use RNA-sequencing to characterize a novel strategy converting fibroblasts into endothelial-like cells through activation of lysosomal activity. Constitutively active MEK2 induces a transcriptional endothelial gene program via sustained MAPK/ERK signaling, leading to enhanced vacuolar ATPase (V-ATPase) activity, lysosomal acidification, extracellular matrix degradation, and angiogenic behavior. Transcriptomic profiling reveals that V-ATPase inhibition impairs induction of endothelial gene expression, whereas pharmacologic V-ATPase activation with EN6 recapitulates key transcriptional features of reprogramming and promotes nuclear translocation of TFEB, a master lysosomal regulator. Consistently, TFEB overexpression, particularly a phospho-deficient mutant, boosts lysosomal gene expression and enhances the endothelial transcriptional signature. This dataset defines a MAPK–V-ATPase–TFEB axis driving endothelial reprogramming at the transcriptional level and provides a resource for exploring the lysosome as a central hub for cell fate transitions

ORGANISM(S): Mus musculus

PROVIDER: GSE339221 | GEO | 2026/09/03

REPOSITORIES: GEO

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V-ATPase-Driven Lysosomal Activation Orchestrates MEK2-Induced Endothelial Reprogramming

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