ERN2 (endoplasmic reticulum to nucleus signaling 2) is a kinase that functions as a key regulator of mucus production and endoplasmic reticulum (ER) stress response through translational control and transcriptional regulation. Primary function: ERN2 acts as an ER stress sensor that induces translational repression via 28S ribosomal RNA cleavage 1 and regulates mucin gene expression through the XBP1S pathway 1. It is also pro-apoptotic, distinguishing it from closely related proteins 2. Mechanism: ERN2 functions downstream of IL-1β signaling and SPDEF transcription factor activation to upregulate MUC5B and MUC5AC mucin expression 3. The ERN2/XBP1S pathway forms a positive feedback bistable loop regulating mucus obstruction 1. ERN2 also interacts with AGR2 under ER stress conditions to drive mucin secretion 4. Disease relevance: ERN2 dysregulation is implicated in idiopathic pulmonary fibrosis (IPF), cystic fibrosis, neutrophilic asthma, and pancreatic ductal adenocarcinoma (PDA), where it promotes excessive mucus production and tumor progression 1345. Clinical significance: ERN2 serves as a prognostic biomarker in lung adenocarcinoma and may be therapeutically targeted via KIRA6 inhibition to ameliorate mucus obstruction-related pathologies 16.