**1. Introduction**

c-JUN-N-terminal kinase (JNK) is a critical mediator of physiological and pathological responses. An upstream MAP kinase signaling cascade from dual specificity MAP3K (e.g., ASK1) and MAP2K (MKK4/7) to serine/threonine MAPK (e.g., JNK, p38) mediate both the initiation of activation of JNK and its sustained activation [1–3]. There is a critical distinction between transient activation of the signaling pathway lasting minutes versus sustained activation lasting hours or more [4]. In this focused review, we will discuss the recent identification of JNK-mitochondrial SAB (SH3BP5)-ROS activation loop in sustaining the MAP kinase cascade, leading to pathological consequences within the context of our interest in liver disease. In addition, we will discuss a variety of factors that regulate or modulate the MAPK pathway from upstream MAP3K, such as apoptosis signal-regulating kinase 1 (ASK1) and mixed lineage kinase 2/3 (MLK2/3), to downstream JNK, SAB, and mitochondrial ROS. This review highlights the pathophysiological mechanism of sustained activation of JNK through JNK-activation loop and opens possible pharmacological interventions for therapeutic targets in the liver, heart, and brain, where SAB has been shown to have an important role.
