GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE339nnn/GSE339221/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE339221GEOGSEfalseV-ATPase-Driven Lysosomal Activation Orchestrates MEK2-Induced Endothelial ReprogrammingDirect 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 transitions2026/09/03GSE339221GSM9890521GSM9890520GSM9890523GSM9890522GSM9890530GSM9890529GSM9890518GSM9890517GSM9890528GSM9890519GSM9890525GSM9890524GSM9890516GSM9890527GSM989052634290339221Mus musculus