Immunosuppression has been found to be closely related to the pathogenesis of<br />sepsis, but the underlying mechanisms have not yet been fully elucidated. In this study,<br />we identified that SH3 domain and nuclear localization signals 1 (SAMSN1), a gene<br />encoding a putative adaptor protein, plays an important role in immunosuppression in<br />sepsis. The expression of SAMSN1 was significantly increased in patients with sepsis<br />and was positively correlated with sepsis mortality. When sepsis occurs, the number of<br />monocyte-macrophages increases significantly, among which SAMSN1 is highly<br />expressed. SAMSN1 binds to KEAP1, causing NRF2 to dissociate from the KEAP1-<br />NRF2 complex and translocate into the nucleus, promoting the transcription of co<br />inhibitory molecules CD48/CD86/CEACAM1, which bind to their corresponding<br />receptors 2B4/CTLA4/TIM3 on the surface of T cells, inducing T cell exhaustion.<br />SAMSN1 blockade alleviated organ injuries and improved survival of septic mice. Our<br />study reveals a novel mechanism that triggers immunosuppression in sepsis and may<br />provide a candidate molecular target for sepsis immunotherapy.

The authors have declared no competing interest.

This work was supported by National Key R&D Program of China (2022YFC2504500 to Yan Kang) andby National Natural Science Foundation of China (82172142 to Fei Xiao, 82272199 to Xuelian Liao).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The observational study using human blood samples for RNA-Seq was approved by Ethics Committee on Biomedical Research, West China Hospital of Sichuan University (registered observational trial: ChiCTR2100047060). The informed consent was obtained from all subjects. This trial was examined and cleared by the Medical Ethics Committee under the ethical approval No.2020641.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The RNA-Seq data used to validate the SAMSN1 mRNA levels in Fig. 1c, d have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2021) in National Genomics Data Center (Nucleic Acids Res 2022), China National Center for Bioinformation/ Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA002988) that are publicly accessible at https:// ngdc.cncb.ac.cn/gsa-human. The RNA-Seq data of RAW264.7-WT and RAW264.7-KO cells in Fig. 6 have been deposited in the NCBI/SRA repository, accession number GSE262688 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE262688). All experimental data and detailed information about this study should be directed to Prof. Wei Zhang (zhangwei197610@wchscu.edu.cn).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE262688

https://ngdc.cncb.ac.cn/gsa-human/browse/HRA002988