ArticleJournal of cardiovascular development and disease2026
Low Shear Stress Promotes Atherosclerosis by Mediating Pathological Accumulation of Endothelial Lipid Droplets via the KLF4/TFEB/ATP1A1 Axis.
Article in Journal of cardiovascular development and disease, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundAtherosclerosis preferentially develops at arterial regions exposed to low shear stress (LSS), highlighting the critical role of local hemodynamic forces in disease initiation and progression. Emerging evidence indicates that endothelial lipid metabolism is a key determinant of vascular homeostasis; however, whether LSS directly regulates endothelial lipid droplets' (LDs) dynamics remains unclear. In particular, the mechano-transduction pathways linking shear stress to lysosome-mediated lipid processing within the endothelium have yet to be defined.
methodsComplementary in vitro flow systems and in vivo atheroprone models were employed to examine the effects of LSS on endothelial lipid metabolism. Endothelial LDs accumulation, lysosome-dependent lipophagy, and atherosclerotic lesion development were systematically assessed under LSS conditions. Mechanistically, molecular profiling and rapamycin-mediated functional rescue were conducted to delineate the role of the KLF4/TFEB/ATP1A1 signaling axis in LSS-induced impairment of lysosome-dependent lipophagy.
resultsWe found that LSS induced pathological accumulation of LDs in vascular endothelial cells, accompanied by a marked suppression of lysosome-dependent lipophagy. Elucidation of the mechanism showed that LSS downregulated the shear-responsive transcription factor KLF4, resulting in aberrant phosphorylation of transcription factor EB (TFEB) and impaired TFEB nuclear translocation. Consequently, the TFEB transcriptional program governing lysosomal function was disrupted, including reduced expression of the TFEB target ATP1A1, leading to defective lysosomal acidification and blockade of lipid autophagic flux. Restoration of the KLF4/TFEB/ATP1A1 axis reactivated lipophagy, alleviated endothelial lipid burden, and significantly attenuated atherosclerotic lesion development.
conclusionsOur findings demonstrate that disruption of the KLF4/TFEB/ATP1A1 signaling pathway mediates LSS-induced impairment of endothelial lipophagy, thereby driving pathological LDs accumulation. This highlights the potential of restoring this axis as a therapeutic strategy to attenuate atherosclerotic progression.
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