Apoptosis signal-regulating kinase 1 (ASK1) (ASK1)

Apoptosis signal-regulating kinase 1 (ASK1), also known as MAP3K5, is a key serine/threonine kinase that mediates "Reactive oxygen species–sensitive apoptosis signaling" (UniProt: Q99683). It functions as a redox-sensitive molecular switch; in its inactive state, ASK1 is bound to the antioxidant protein thioredoxin (Trx). Upon the accumulation of reactive oxygen species (ROS), Trx becomes oxidized and dissociates, allowing ASK1 to autophosphorylate and activate downstream mitogen-activated protein kinases (MAPKs), specifically JNK and p38 (PubMed: 10409703). This signaling cascade is a critical driver of apoptosis, inflammation, and fibrosis in response to cellular stress. Pathological overactivation of the ASK1 pathway is implicated in several chronic conditions, including non-alcoholic steatohepatitis (NASH), diabetic kidney disease, and various neurodegenerative and cardiovascular diseases (PubMed: 28844882). Consequently, ASK1 has been targeted by pharmaceutical developers using small-molecule inhibitors like selonsertib (GS-4997) to prevent cell death and tissue damage. While early clinical trials showed promise in inflammatory and fibrotic diseases, achieving significant clinical endpoints in late-stage trials has proven challenging (ClinicalTrials.gov: NCT02885350).

Other names

MAP3K5Mitogen-activated protein kinase kinase kinase 5MAPKKK5MEKK5Reactive oxygen species–sensitive apoptosis signaling

Small molecule inhibition of the ASK1 kinase domain to block downstream JNK and p38 MAPK activation.