Petrovic Vladimir, Whiteman Andrew, Peach Matt, Kim Sam, Malkov Vladislav A, Budas Grant, Billin Andrew N
Gilead Sciences Inc., Foster City, CA, USA.
BMC Nephrol. 2025 May 15;26(1):244. doi: 10.1186/s12882-025-04166-4.
Oxidative stress is a driver of acute and chronic kidney injury. Selonsertib is a clinical stage antagonist of ASK1 (MAP3K5), a serine/threonine kinase that is a mediator of oxidative stress signaling pathways. Selonsertib has demonstrated promising effects on preserving kidney function in the Phase2b Diabetic Kidney Disease (DKD) MOSAIC trial. However, little is known about the biological effects of ASK1 inhibition by selonsertib and its potential mechanism of action in DKD. We identified a plasma proteome signature of selonsertib activity that implicates numerous signaling pathways that regulate fibrosis, inflammation and oxidative stress response demonstrating translation of non-clinical models to the clinic. We further demonstrate that the effects of selonsertib on the plasma proteome are most pronounced in a subset of patients with poor baseline kidney function but who respond well to selonsertib treatment. This observation has implications for the future development of ASK1 inhibitors in a distinct patient population with DKD.
氧化应激是急性和慢性肾损伤的一个驱动因素。塞洛西布是ASK1（丝裂原活化蛋白激酶激酶5）的临床阶段拮抗剂，ASK1是一种丝氨酸/苏氨酸激酶，是氧化应激信号通路的介质。在2b期糖尿病肾病（DKD）MOSAIC试验中，塞洛西布已显示出对保护肾功能有良好效果。然而，关于塞洛西布抑制ASK1的生物学效应及其在DKD中的潜在作用机制知之甚少。我们确定了塞洛西布活性的血浆蛋白质组特征，这涉及许多调节纤维化、炎症和氧化应激反应的信号通路，表明非临床模型可转化至临床。我们进一步证明，塞洛西布对血浆蛋白质组的影响在基线肾功能较差但对塞洛西布治疗反应良好的一部分患者中最为明显。这一观察结果对ASK1抑制剂在不同DKD患者群体中的未来开发具有启示意义。
