Extracellular vesicles (EVs) are tools for intercellular communication, mediating molecular transport processes. Emerging studies have revealed that EVs are significantly involved in immune processes, including sepsis. Sepsis, a dysregulated immune response to infection, triggers systemic inflammation and multi-organ dysfunction, posing a life-threatening condition. Although extensive research has been conducted on animals, the complex inflammatory mechanisms that cause sepsis-induced organ failure in humans are still not fully understood. Recent studies have focused on secreted exosomes, which are small extracellular vesicles from various body cells, and have shed light on their involvement in the pathophysiology of sepsis. During sepsis, exosomes undergo changes in content, concentration, and function, which significantly affect the metabolism of endothelia, cardiovascular functions, and coagulation. Investigating the role of exosome content in the pathogenesis of sepsis shows promise for understanding the molecular basis of human sepsis. This review explores the contributions of activated immune cells and diverse body cells’ secreted exosomes to vital organ dysfunction in sepsis, providing insights into potential molecular biomarkers for predicting organ failure in septic shock.

TEAD4 is a transcription factor that plays a crucial role in the Hippo pathway by regulating the expression of genes related to proliferation and apoptosis. It is also involved in the maintenance and differentiation of the trophectoderm during pre- and post-implantation embryonic development. An alternative promoter for the TEAD4 gene was identified through epigenetic profile analysis, and a new transcript from the intronic region of TEAD4 was discovered using the 5’RACE method. The transcript of the novel promoter encodes a TEAD4 isoform (TEAD4-ΔN) that lacks the DNA-binding domain but retains the C-terminal protein–protein interaction domain. Gene expression studies, including end-point PCR and Western blotting, showed that full-length TEAD4 was present in all investigated tissues. However, TEAD4-ΔN was only detectable in certain cell types. The TEAD4-ΔN promoter is conserved throughout evolution and demonstrates transcriptional activity in transient-expression experiments. Our study reveals that TEAD4 interacts with the alternative promoter and increases the expression of the truncated isoform. DNA methylation plays a crucial function in the restricted expression of the TEAD4-ΔN isoform in specific tissues, including the umbilical cord and the placenta. The data presented indicate that the DNA-methylation status of the TEAD4-ΔN promoter plays a critical role in regulating organ size, cancer development, and placenta differentiation.

Exosomes carry bioactive macromolecules driving sepsis pathogenesis, but the mechanisms underlying macrophage-to-hepatocyte communication during systemic inflammation remain poorly understood. We investigated how sepsis-induced macrophage exosomes are involved in remote intercellular crosstalk with hepatic cells via transcription factor-encoding mRNA cargo. Human monocytic THP-1 macrophages were stimulated with lipopolysaccharide (LPS), followed by exosome isolation, recipient cell uptake verification, and high-throughput RNA sequencing cargo analysis. To functionally reconstruct downstream signaling in recipient cells, exosome-enriched MAFB mRNA was transiently overexpressed in a HepG2 cell model, with subsequent expression changes mapped at both the transcript and protein levels using quantitative PCR and Western blot analyses. This ectopic MAFB expression directly upregulates the expression of microRNA-155 (miR-155). Crucially, elevated miR-155 acts as a post-transcriptional repressor that directly targets and downregulates JARID2 and H3F3A mRNAs and their corresponding protein products within the liver cells, orchestrating a “repressor-of-repressors” disinhibition cascade that drives net chromatin remodeling and activation of downstream hepatic target genes. This study demonstrates that sepsis alters exosomal transcription factor mRNA cargo and delineates a mechanistic downstream pathway—MAFB → ↑miR155 → ↓Jarid2 & ↓H3F3A → Chromatin Remodeling → Downstream Hepatic Gene Activation pathway—that provides novel, specific molecular checkpoints for therapeutic intervention in sepsis-induced liver injury.