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BACKGROUND Some adipocytes undergo dedifferentiation after fat transplantation, and this may affect the survival of fat grafts. However, this has not been adequately studied. OBJECTIVES This study aimed to clarify the effect of promoting the dedifferentiation of mature adipocytes on the survival of fat grafts. METHODS Mature adipocytes and adipose stem cells (ASCs) were treated with OSI-906 in vitro, and then we evaluated the dedifferentiation of mature adipocytes and the proliferation of ASCs. In the in vivo experiment, we compared human lipoaspirates mixed with phosphate-buffered saline (group A) or OSI-906 (group B) in nude mice. Grafts were harvested at 2, 8, and 12 weeks, and volume retention rate, histologic, and immunohistochemical analyses were conducted. RESULTS OSI-906 can promote the dedifferentiation of mature adipocytes and inhibit the proliferation of ASCs. At 12 weeks, group B (62.3%±7.61%) showed a better volume retention rate than group A (47.75%±6.11%) (p < 0.05). Moreover, viable adipocytes and vascularization showed greater improvement in group B than in group A. CONCLUSIONS This study suggests that promoting the dedifferentiation of mature adipocytes can improve the survival rate and quality of fat grafts.