The canonical ER stress IRE1α/XBP1 pathway mediates skeletal muscle wasting during pancreatic cancer cachexia

Cancer cachexia is a debilitating syndrome characterized by the progressive loss of skeletal muscle mass with or without fat loss. Recent studies have implicated dysregulation of the endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) pathways in skeletal muscle under various conditions, including cancer. In this study, we demonstrate that the IRE1α/XBP1 branch of the UPR promotes activation of the ubiquitin–proteasome system, autophagy, JAK-STAT3 signaling, and fatty acid metabolism in the skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Moreover, we show that the IRE1α/XBP1 pathway is a key contributor to muscle wasting. Skeletal muscle-specific deletion of the XBP1 transcription factor significantly attenuates tumor-induced muscle atrophy. Mechanistically, transcriptionally active XBP1 binds to the promoter regions of genes such as Map1lc3b , Fbxo32 , and Il6 , which encode proteins known to drive muscle proteolysis. Pharmacological inhibition of IRE1α using 4µ8C in KPC tumor-bearing mice attenuates cachexia-associated molecular changes and improves muscle mass and strength. Collectively, our findings suggest that targeting IRE1α/XBP1 pathway may offer a therapeutic strategy to counteract muscle wasting during pancreatic cancer-induced cachexia.