A recent study featured in Nature reveals a promising drug candidate, UH15-38, that significantly reduces lung damage and increases survival rates in mice with influenza A virus (IAV) infection by inhibiting necroptosis, a type of inflammatory cell death [1]. The research team led by Gregory Cuny, Paul Thomas, Alexei Degterev and Siddharth Balachandran showed that UH15-38 specifically targets and deactivates RIPK3, an essential kinase in the necroptosis pathway. This discovery not only unveils new pathways involved in inflammatory diseases, such as severe influenza A infection, but also highlights the potential of this drug to treat a wide array of inflammatory viral or non-viral conditions.

Apoptosis was considered the only form of cell death, but novel mechanisms, such as necroptosis, has broadened our comprehension of cell death [2]. Necroptosis plays a role in several pathophysiological scenarios, such as development, immune responses, and inflammatory conditions [3]. Necroptosis involves a cascade of signaling events that culminate in necrotic-like death. At the heart of this process is the activation of receptor-interacting protein kinase-1 (RIPK1) [4] and RIPK3 [5], forming the necrosome complex, that, in turn, activates the Mixed-Lineage-Kinase-Domain-Like protein (MLKL), causing it to oligomerize on the plasma membrane, where it leads to cell lysis [6]. The initiation of necroptosis is carefully regulated by various elements, including death receptors like tumor necrosis factor receptor 1 (TNFR1) and the level of caspase-8, which normally prevents necroptosis by deactivating RIPK1 and RIPK3. However, necroptosis can occur without restraint under specific conditions, e.g. low caspase-8 activity or when certain triggers are present. This is in fact the case in IAV-infected lung epithelial cells, in which caspase-8 is dramatically reduced [7].

《自然》杂志最近的一项研究揭示了一种有前途的候选药物 UH15-38，它通过抑制坏死性凋亡（一种炎症细胞死亡），显着减少甲型流感病毒 (IAV) 感染小鼠的肺损伤并提高存活率 [1]。由 Gregory Cuny、Paul Thomas、Alexei Degterev 和 Siddharth Balachandran 领导的研究小组表明，UH15-38 特异性靶向并失活 RIPK3（坏死性凋亡途径中的一种重要激酶）。这一发现不仅揭示了与严重甲型流感感染等炎症性疾病相关的新途径，而且还凸显了该药物治疗多种炎症性病毒或非病毒性疾病的潜力。

细胞凋亡被认为是细胞死亡的唯一形式，但坏死性凋亡等新机制拓宽了我们对细胞死亡的理解[2]。坏死性凋亡在多种病理生理学情况中发挥作用，例如发育、免疫反应和炎症状况[3]。坏死性凋亡涉及一系列信号事件，最终导致坏死样死亡。该过程的核心是受体相互作用蛋白激酶 1 (RIPK1) [4] 和 RIPK3 [5] 的激活，形成坏死体复合物，进而激活混合谱系激酶结构域蛋白 (MLK​​L)，导致其在质膜上寡聚，从而导致细胞裂解 [6]。坏死性凋亡的启动受到多种因素的仔细调节，包括肿瘤坏死因子受体 1 (TNFR1) 等死亡受体和 caspase-8 的水平，后者通常通过停用 RIPK1 和 RIPK3 来防止坏死性凋亡。然而，在特定条件下，例如 caspase-8 活性低或存在某些触发因素时，坏死性凋亡可能不受限制地发生。事实上，在 IAV 感染的肺上皮细胞中就是这种情况，其中 caspase-8 显着减少 [7]。