Background <p>Autologous fat transplantation (AFT) is widely used in aesthetic and reconstructive surgery, but its long-term outcomes remain unpredictable because of complications such as oil cyst formation, the underlying mechanisms of which are poorly understood. This study aimed to investigate the pathogenesis of oil cyst development in grafted fat and explore potential pharmacological interventions.</p> Methods <p>We established a refined and reproducible mouse model of fat grafting to simulate post transplantation oil cyst formation. Molecular signaling pathways were analyzed using immunohistochemistry and western blotting. The role of necroptosis was further evaluated through genetic and pharmacological approaches. Clinical human samples of oil cysts obtained from patients who underwent AFT were also examined to validate the findings in the mouse model. Finally, the effects of metformin, an FDA-approved drug, on necroptosis and oil cyst formation were evaluated in the experimental model.</p> Results <p>Our results demonstrated that necroptosis, predominantly in adipocytes, is closely associated with oil cyst formation. Activation of the RIPK3–MLKL signaling axis was identified as the key molecular mechanism promoting necroptosis in grafted fat. These findings were corroborated in human oil cyst samples, in which the same pathway was activated. Treatment with metformin significantly inhibited RIPK3–MLKL-mediated necroptosis and reduced oil cyst formation in the mouse model.</p> Conclusions <p>Necroptosis is an important pathological process during oil cyst development following autologous fat transplantation. The findings of this study suggest that targeting the necroptotic pathway, for instance, with metformin, could offer a viable therapeutic strategy to improve the survival and stability of grafted fat, thereby improving the long-term efficacy of fat transplantation procedures.</p>