# Heme drives cardiac endothelial senescence in sepsis via STING activation

## TL;DR

Heme contributes to heart damage in sepsis by activating STING, and clearing heme could help treat this condition.

## Contribution

Heme is identified as a novel STING ligand driving endothelial senescence in sepsis, with therapeutic implications.

## Key findings

- Elevated heme levels correlate with endothelial senescence and impaired cardiac function in sepsis.
- Heme activates STING, promoting endothelial senescence through polymerization and signaling.
- STING inhibition or increased hemopexin reduces cardiac endothelial senescence in septic mice.

## Abstract

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.