Necroptosis is a regulated form of necrotic cell death that is mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1)， RIPK3 and mixed-lineage kinase domain-like protein (MLKL)， which mediates necroptotic signal transduction induced by tumor necrosis factor (TNF). Although many target proteins for necroptosis have been identified， no report had indicated that FK506-binding protein 12 (FKBP12， also known as FKBP1A)， an endogenous protein that regulates protein folding and conformation alteration， is involved in mediating necroptosis. In this study， we found that FKBP12 acts as a novel target protein in mediating necroptosis and the related systemic inflammatory response syndrome triggered by TNF. The mechanistic study discovered that FKBP12 is essential for initiating necrosome formation and RIPK1-RIPK3-MLKL signaling pathway activation in response to TNF receptor 1 ligation. In addition， FKBP12 is indispensable for RIPK1 and RIPK3 expression and subsequent spontaneous phosphorylation， which are essential processes for initial necrosome formation and necroptotic signal transduction; therefore， FKBP12 may target RIPK1 and RIPK3 to mediate necroptosis and Collectively， our data demonstrate that FKBP12 could be a potential therapeutic target for the clinical treatment of necroptosis-associated diseases.