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.