Chemical mimetics of the N-degron pathway alleviate systemic inflammation by activating mitophagy and immunometabolic remodeling

Abstract

Sepsis: chemical modulation of selective autophagy alleviates systemic inflammation Sepsis is a life-threatening condition that occurs when the body’s response to infection damages its own organs. Autophagy protects the body by degrading harmful materials in the cell using the lysosome. It has been an outstanding question whether autophagy can fight systemic inflammation in sepsis. Researchers in South Korea led by Eun-Kyeong Jo at Chungnam National University and Yong Tae Kwon at Seoul National University developed small molecule chemicals that target the autophagic receptor p62/SQSTSM-1/Sequestosome-1 to induce therapeutic efficacy during septic responses. In a mouse model of septic shock, these orally administrative compounds halted the production of proinflammatory molecules and reduced oxidative stress in mitochondria by facilitating the autophagic turnover of damaged mitochondria. Chemical modulation of p62 is now emerging as a therapeutic strategy to treat sepsis responsible for 11 million deaths a year.