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The pentose phosphate pathway (PPP) plays an essential role in cell proliferation via production of NADPH.Smooth muscle (SM) 22α protein is involved in the regulation of vascular smooth muscle cell (VSMC) phenotypes.Here, we identify the relationship between NADPH production and SM22α activity in the development and progression of vascular diseases.We showed that the expression and activity of Glucose-6-phosphate dehydrogenase (G6PD) is promoted in PDGF-BB-induced proliferative VSMCs.PDGF-BB induced G6PD membrane translocation and activation in a SM22αK21 ubiquitination-dependent manner.The ubiquitinated SM22α interacted with G6PD, and mediated G6PD membrane translocation.Furthermore, we found that TNF receptor associated factor (TRAF) 6 mediated SM22 a K21 ubiquitination in a K63-1inked manner upon PDGF-BB stimulation.Knockdown of TRAF6 decreased the membrane translocation and activity of G6PD, parallel with reduced SM22α K21 ubiquitination.Increased NADPH generation enhanced VSMC viability, and reduced apoptosis in vivo and in vitro via glutathione (GSH) homeostasis.We provide evidence that TRAF6-induced SM22α ubiquitination maintains VSMC survival through increase in G6PD activity and NADPH production.