New therapeutic approaches for chronic inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis are needed because current treatments are often suboptimal in terms of both efficacy and the risks of serious adverse events. Inhibitor of apoptosis proteins (IAPs) are E3 ubiquitin ligases that inhibit cell death pathways and are themselves inhibited by second mitochondria-derived activator of caspases (SMAC). SMAC mimetics (SMs), small-molecule antagonists of IAPs, are being evaluated as cancer therapies in clinical trials. IAPs are also crucial regulators of inflammatory pathways because they influence both the activation of inflammatory genes and the induction of cell death through the receptor-interacting serine-threonine protein kinases (RIPKs), nuclear factor κB (NF-κB)-inducing kinase, and mitogen-activated protein kinases (MAPKs). Furthermore, there is an increasing interest in specifically targeting the substrates of IAP-mediated ubiquitylation, especially RIPK1, RIPK2, and RIPK3, as druggable nodes in inflammation control. Several studies have revealed an anti-inflammatory potential of RIPK inhibitors that either block inflammatory signaling or block the form of inflammatory cell death known as necroptosis. Expanding research on innate immune signaling through pattern recognition receptors that stimulate proinflammatory NF-κB and MAPK signaling may further contribute to uncovering the complex molecular roles used by IAPs and downstream RIPKs in inflammatory signaling. This may benefit and guide the development of SMs or selective RIPK inhibitors as anti-inflammatory therapeutics for various chronic inflammatory conditions.

中文翻译：

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SMAC模拟物和RIPK抑制剂可作为慢性炎性疾病的治疗剂。

对于慢性炎性疾病，例如炎性肠病，类风湿性关节炎和牛皮癣，需要新的治疗方法，因为就疗效和严重不良事件的风险而言，当前的治疗常常是次优的。凋亡蛋白（IAP）抑制剂是E3泛素连接酶，可抑制细胞死亡途径，并本身被第二个线粒体衍生的胱天蛋白酶（SMAC）激活剂抑制。IAP的小分子拮抗剂SMAC模拟物（SMs）正在临床试验中评估为癌症治疗方法。IAP也是炎症途径的关键调节因子，因为它们通过与受体相互作用的丝氨酸-苏氨酸蛋白激酶（RIPK），核因子κB（NF-κB）诱导激酶，影响炎症基因的激活和细胞死亡的诱导，和丝裂原激活的蛋白激酶（MAPK）。此外，人们越来越关注将IAP介导的泛素化（尤其是RIPK1，RIPK2和RIPK3）的底物作为炎症控制中的可药物治疗靶点。几项研究揭示了RIPK抑制剂的抗炎潜力，它可以阻断炎症信号传导或阻断被称为坏死性坏死的炎症细胞死亡。通过刺激促炎性NF-κB和MAPK信号传导的模式识别受体对先天性免疫信号传导的扩展研究可能进一步有助于揭示IAP和下游RIPK在炎症信号传导中所使用的复杂分子作用。这可能有益于并指导SM或选择性RIPK抑制剂作为各种慢性炎性疾病的抗炎治疗剂的开发。