Celastrol inhibits necroptosis by attenuating the RIPK1/RIPK3/MLKL pathway and confers protection against acute pancreatitis in mice

by Selleckchem | May 18 2023

Necroptosis is a necrotic form of regulated cell death, which is primarily mediated by the receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) pathway in a caspase-independent manner. Necroptosis has been found to occur in virtually all tissues and diseases evaluated, including pancreatitis. Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium wilfordii (thunder god vine), possesses potent anti-inflammatory and anti-oxidative activities. Yet, it is unclear whether celastrol has any effects on necroptosis and necroptotic-related diseases. Here we showed that celastrol significantly suppressed necroptosis induced by lipopolysaccharide (LPS) plus pan-caspase inhibitor (IDN-6556) or by tumor-necrosis factor-α in combination with LCL-161 (Smac mimetic) and IDN-6556 (TSI). In these in vitro cellular models, celastrol inhibited the phosphorylation of RIPK1, RIPK3, and MLKL and the formation of necrosome during necroptotic induction, suggesting its possible action on upstream signaling of the necroptotic pathway. Consistent with the known role of mitochondrial dysfunction in necroptosis, we found that celastrol significantly rescued TSI-induced loss of mitochondrial membrane potential. TSI-induced intracellular and mitochondrial reactive oxygen species (mtROS), which are involved in the autophosphorylation of RIPK1 and recruitment of RIPK3, were significantly attenuated by celastrol. Moreover, in a mouse model of acute pancreatitis that is associated with necroptosis, celastrol administration significantly reduced the severity of caerulein-induced acute pancreatitis accompanied by decreased phosphorylation of MLKL in pancreatic tissues. Collectively, celastrol can attenuate the activation of RIPK1/RIPK3/MLKL signaling likely by attenuating mtROS production, thereby inhibiting necroptosis and conferring protection against caerulein-induced pancreatitis in mice.

Comments：

The passage describes a study that investigated the effects of celastrol, a compound derived from Tripterygium wilfordii, on necroptosis, a form of regulated cell death mediated by the RIPK1/RIPK3/MLKL pathway. The study used in vitro models of necroptosis induced by lipopolysaccharide (LPS) and caspase inhibitors, as well as a mouse model of acute pancreatitis associated with necroptosis.

The results showed that celastrol significantly suppressed necroptosis in the in vitro models by inhibiting the phosphorylation of RIPK1, RIPK3, and MLKL and the formation of the necrosome, which is involved in necroptotic signaling. Celastrol also attenuated mitochondrial dysfunction associated with necroptosis, including the loss of mitochondrial membrane potential and the production of reactive oxygen species (ROS).

In the mouse model of acute pancreatitis, celastrol administration significantly reduced the severity of the disease and decreased the phosphorylation of MLKL in pancreatic tissues, suggesting a protective effect against necroptosis.

Overall, the study suggests that celastrol has potential as a therapeutic agent for necroptotic-related diseases, including acute pancreatitis.