# MYSM1-mediated epigenetic modification dysregulation leads to immunosuppression and secondary infections in sepsis

## TL;DR

This study shows that MYSM1, an enzyme involved in epigenetic changes, contributes to immune suppression in sepsis, and targeting it could help prevent secondary infections.

## Contribution

The study identifies MYSM1-mediated epigenetic dysregulation as a novel driver of sepsis-induced immunosuppression and suggests a new therapeutic approach.

## Key findings

- MYSM1 regulates histone ubiquitination, which is central to sepsis-induced immunosuppression.
- Deleting the N-terminal domain of MYSM1 improves macrophage function and survival in septic mice.
- Targeting MYSM1 could reverse immune dysfunction and prevent secondary infections in sepsis.

## Abstract

Sepsis is a life-threatening condition characterized by a dysregulated immune response to infection, often leading to organ dysfunction and even death. During the recovery phase of sepsis, patients frequently exhibit impaired antimicrobial function of immune cells, which exacerbates the state of immunosuppression and increases the risk of secondary infections. However, therapeutic strategies targeting sepsis-induced immunosuppression have yet to achieve breakthrough progress, with the core challenge lying in the significant gaps in understanding the molecular mechanisms underlying immunosuppression. In this study, we integrated clinical samples, mouse models, and molecular mechanisms to reveal that the reduction in macrophage function and epigenetic dysregulation, particularly histone ubiquitination, are central drivers of sepsis-induced immunosuppression. Further investigation demonstrated that MYSM1, a deubiquitinase, plays a pivotal role in regulating this ubiquitination process. Targeted deletion of the N-terminal domain of MYSM1 markedly enhances the inflammatory response during the early phase of secondary infection in sepsis, facilitating bacterial clearance and significantly mitigating tissue damage in the late phase of secondary infection, thereby improving the survival outcomes in mice. Overall, our study elucidates the role of MYSM1-mediated dysregulation of epigenetic modifications in the immune response during the late phase of sepsis, providing a novel therapeutic approach for addressing sepsis-related immune dysfunction.

Sepsis is a severe and often fatal condition caused by an uncontrolled immune response to infection. Although early treatment can control the initial inflammation, many patients enter a stage of immune paralysis during recovery, which makes them highly susceptible to secondary infections. The mechanisms driving this immunosuppressive state remain poorly understood, hindering the development of effective therapies. In this study, we combined clinical samples, mouse models, and molecular experiments to uncover how the histone deubiquitinase MYSM1 contributes to sepsis-induced immunosuppression. We found that MYSM1-mediated dysregulation of histone ubiquitination leads to impaired macrophage antimicrobial function and weakened immune responses. Deletion of the N-terminal domain of MYSM1 restored macrophage activity, enhanced bacterial clearance, and improved survival in septic mice, demonstrating that MYSM1 is a key regulator of immune reprogramming during sepsis. These findings provide new insights into the epigenetic mechanisms underlying sepsis-induced immune dysfunction and identify MYSM1 as a promising therapeutic target for reversing immunosuppression and preventing secondary infections in septic patients.