TSPO exacerbates sepsis-induced cardiac dysfunction by inhibiting p62-Mediated autophagic flux via the ROS-RIP1/RIP3-exosome axis

Septic cardiomyopathy (SCM) is a critical complication of sepsis, primarily attributed to mitochondrial dysfunction and impaired autophagic flux. This study explores the role of translocator protein (TSPO) in SCM pathogenesis and assesses its potential as a therapeutic target. We identified increased TSPO expression in plasma samples from sepsis patients, with further validation in septic rats and LPS-stimulated H9C2 cardiomyocytes. Elevated TSPO disrupted mitochondrial function, leading to increased reactive oxygen species (ROS) production and activation of the RIP1/RIP3 pathway, which hindered p62-positive autophagosome degradation and promoted inflammation. Moreover, exosome release containing TSPO-positive autophagosomes into plasma may exacerbate systemic inflammation. NADH, identified as a TSPO-binding molecule, restored autophagic flux, improved mitochondrial function, and enhanced cardiac performance and survival in septic rats. These findings suggest that targeting TSPO with NADH could alleviate mitochondrial dysfunction and inflammatory responses in SCM, providing a promising therapeutic strategy for sepsis-induced cardiac injury.