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However, the molecular mechanisms remain unclear. This study highlights the critical role of cytosolic Phospholipase A2 (cPLA2)\/ Yin Yang 1 (YY1)\/ carnitine palmitoyltransferase 1b (CPT1B)\u00a0signaling in coordinating VSMC mechanical activation by inhibiting fatty acid \u03b2\u2010oxidation. Metabolomic analysis showed that a 15%\u20131\u00a0Hz arterial cyclic stretch, compared to a 5%\u20131\u00a0Hz venous stretch, increased long\u2010chain fatty acids in VSMCs. cPLA2, identified as a mechanoresponsive molecule, produces excessive arachidonic acid (ArAc) under the 15%\u20131\u00a0Hz stretch, inhibiting CPT1B expression, a key enzyme in fatty acid \u03b2\u2010oxidation. ArAc promotes transcription factor YY1 degradation, downregulating CPT1B. Inadequate fatty acid oxidation caused by knockdown of CPT1B or YY1, or etomoxir treatment, increased nuclear membrane tension, orchestrating the activation of cPLA2. 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