Tingting Li, Peilin Zhu, Jialing Wang, Tao Zhang, J. S. Adams, Fei Tu, Chloe G. Garbe, Xiaojin Zhang, Li Liu, Krishna Singh, David L. Williams, Chuanfu Li, Xiaohui Wang
CSF-HPX may be a candidate biomarker associated with hemorrhage burden and risk of secondary sepsis after ICH. These findings are exploratory and require validation in larger prospective studies.
Sepsis-induced cardiac dysfunction is a major contributor to sepsis-related mortality, and many patients continue to experience long-term cardiac complications after recovery. Here, we demonstrate that cardiac senescence is a key feature of sepsis-associated cardiac dysfunction, with endothelial cells identified as the predominant senescent population in septic cardiac tissue. However, the pathogenic drivers of endothelial senescence in sepsis remain poorly characterized. Among potential mediators, we found that elevated levels of heme, a byproduct of hemolysis, strongly correlate with increased endothelial senescence and impaired cardiac function. Mechanistic studies revealed that heme acts as a novel ligand for STING, exacerbating bacterial infection-induced STING polymerization and activation, thereby promoting endothelial senescence. Notably, either STING inhibition or enhanced heme clearance via increased hemopexin expression significantly alleviated cardiac endothelial senescence and facilitated cardiac functional recovery in septic mice. These findings identify heme as a critical pathogenic driver of endothelial senescence and highlight heme clearance as a promising therapeutic strategy for mitigating sepsis-induced cardiac dysfunction.