Sepsis-Related Liver Dysfunction Has a 61.5% Mortality Rate; Korean Researchers Identify Key Pathway

With sepsis-related liver dysfunction carrying a mortality rate of 61.5%, Korean researchers have identified a key molecular pathway that drives the condition, pointing to a potential new treatment approach.

According to a study published on the 28th in the international journal Science Advances, researchers found in an animal model of sepsis that transglutaminase 2 (TG2), a cross-linking enzyme, activates macrophages and causes liver inflammation.

The researchers said pharmacological inhibition of TG2 increased survival and reduced multiorgan inflammation, and identified the liver as a major therapeutic target organ.

Specifically, when TG2 activity increased in macrophages, the enzyme cross-linked a protein called vimentin, promoting its oligomerization and intermediate filament remodeling. Genetic deletion of either TG2 or vimentin suppressed cytokine production by macrophages and alleviated inflammation induced by lipopolysaccharide (LPS).

In particular, proteasomes in vimentin-deficient macrophages were more likely to move to insoluble protein aggregates, accelerating the degradation of proinflammatory factors such as Traf6 and thereby suppressing nuclear factor kappa B (NF-κB) signaling.

Through proteomic analysis, the researchers also discovered a previously unknown transport pathway for clearing inflammatory aggregates, mediated by Rab27a-positive vesicles. The findings are considered to identify the TG2-vimentin axis linking cytoskeletal remodeling with inflammatory signaling.

The World Health Organization (WHO) designated sepsis a global health priority in 2017. The first Global Report on Sepsis, published in 2020, estimated that about 11 million people die from sepsis each year, accounting for 20% of deaths worldwide and making it the leading cause of death, surpassing cancer.

The lethality of sepsis stems primarily from dysregulation of the immune response, which leads to widespread inflammation and multiorgan failure. The liver is particularly vulnerable to sepsis-related injury because it plays a key role in metabolic regulation and immune surveillance.

Sepsis-related liver dysfunction worsens systemic inflammation and is considered an independent predictor of poor clinical outcomes. However, despite major advances in critical care, the condition remains an unmet therapeutic need, with a mortality rate of 61.5%—far higher than that of other sepsis-related organ failures.

Current management strategies borrowed from other liver diseases have limited effectiveness because of a lack of understanding of disease-specific mechanisms. In a recent autopsy analysis, the researchers identified distinctive pathological features, including disruption of the bile canalicular microstructure and a strong association with intra-abdominal infection and persistent gut microbiome imbalance, unlike ischemic or toxic liver injury.

Macrophages play a key role in initiating and amplifying organ-specific injury signals. When macrophages recognize pathogen molecules such as LPS or double-stranded RNA, they are activated through Toll-like receptor (TLR) signaling pathways and secrete large amounts of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and IL-1β.

The levels of these cytokines are directly associated with the severity of liver injury and early mortality in sepsis. However, clinical trials targeting individual cytokines or upstream recognition pathways have yet to produce effective treatments.

The researchers said the findings could help advance new treatment strategies for sepsis-related liver dysfunction by targeting the TG2-vimentin axis, which regulates macrophage activation.