Abstract
Introduction: Ubiquitination and immune regulation play an important role in sepsis. The purpose of this study was to explore the potential value of ubiquitination- and immune-related genes in sepsis and develop a risk score prognostic model based on sepsis ubiquitination- and immune-related genes for accurate outcome prediction and better treatment guidance. Methods: Differential expression and univariate Cox analyses were used to identify ubiquitination- and immune-related DEGs related to prognosis, and then a risk model was constructed using LASSO regression analysis. Subsequently, Kaplan-Meier analysis, time-dependent ROC curve analysis, immune cell infiltration analysis, functional enrichment analysis, drug prediction, and molecular docking were performed. Results: A total of 4 ubiquitination- and immune-related DEGs related to the prognosis of sepsis were identified. A risk score model was constructed based on these 4 genes. The proportion of death samples in the high-risk score group was higher and the OS was worse. The risk score was an independent prognostic factor for sepsis. The time-dependent ROC curve indicated that the risk score model had good predictive ability. The results of ssGSEA and GSEA showed that most immune cell infiltration levels decreased and immune- and inflammation-related pathways showed inhibitory states in the high-risk group. In addition, 7 protein-drug docking results were obtained. The binding energy of LCK and JNJ-26483327 was the lowest. Conclusion: The 4 ubiquitination- and immune-related model genes may play an important role in sepsis by regulating immune cell infiltration and immune- and inflammatory-related pathways. The model constructed based on these 4 genes has good predictive value, which may help clinical doctors better evaluate the prognosis of sepsis patients and develop personalized treatment plans.
Journal Section:
Experimental Immunology
References
1.
Singer
M
, Deutschman
CS
, Seymour
CW
, Shankar-Hari
M
, Annane
D
, Bauer
M
, et al. The Third International consensus definitions for sepsis and septic shock (Sepsis-3)
. JAMA
. 2016
;315
(8
):801
–10
. 2.
Fleischmann-Struzek
C
, Mellhammar
L
, Rose
N
, Cassini
A
, Rudd
KE
, Schlattmann
P
, et al. Incidence and mortality of hospital- and ICU-treated sepsis: results from an updated and expanded systematic review and meta-analysis
. Intensive Care Med
. 2020
;46
(8
):1552
–62
. 3.
Yang
H
, Cui
Y
, Peng
W
, Zhu
F
, Ma
S
, Rao
M
, et al. Identification of molecular subtypes and a novel prognostic model of sepsis based on ferroptosis-associated gene signature
. Biomolecules
. 2022
;12
(10
):1479
. 4.
Zheng
Y
, Liu
B
, Deng
X
, Chen
Y
, Huang
Y
, Zhang
Y
, et al. Construction and validation of a robust prognostic model based on immune features in sepsis
. Front Immunol
. 2022
;13
:994295
. 5.
Swatek
KN
, Komander
D
. Ubiquitin modifications
. Cell Res
. 2016
;26
(4
):399
–422
. 6.
Chen
ZJ
, Sun
LJ
. Nonproteolytic functions of ubiquitin in cell signaling
. Mol Cell
. 2009
;33
(3
):275
–86
. 7.
Liao
Y
, Zhang
W
, Zhou
M
, Zhu
C
, Zou
Z
. Ubiquitination in pyroptosis pathway: a potential therapeutic target for sepsis
. Cytokine Growth Factor Rev
. 2024
;80
:72
–86
. 8.
Wang
J
, He
Y
, Zhou
D
. The role of ubiquitination in microbial infection induced endothelial dysfunction: potential therapeutic targets for sepsis
. Expert Opin Ther Targets
. 2023
;27
(9
):827
–39
. 9.
Li
Y
, Yu
J
, Zeng
Z
, Lin
W
. Regulation of ubiquitination in sepsis: from PAMP versus DAMP to peripheral inflammation and cell death
. Front Immunol
. 2024
;15
:1513206
. 10.
Hu
B
, Ge
C
, Zhu
C
. Ubiquitin-specific peptidase 18 negatively regulates and inhibits lipopolysaccharide-induced sepsis by targeting transforming growth factor-β-activated kinase 1 activity
. Int Immunol
. 2021
;33
(9
):461
–8
. 11.
Wu
L
, Ai
ML
, Feng
Q
, Deng
S
, Liu
ZY
, Zhang
LN
, et al. Serum glial fibrillary acidic protein and ubiquitin C-terminal hydrolase-L1 for diagnosis of sepsis-associated encephalopathy and outcome prognostication
. J Crit Care
. 2019
;52
:172
–9
. 12.
Boomer
JS
, Green
JM
, Hotchkiss
RS
. The changing immune system in sepsis: is individualized immuno-modulatory therapy the answer
. Virulence
. 2014
;5
(1
):45
–56
. 13.
Nedeva
C
. Inflammation and cell death of the innate and adaptive immune system during sepsis
. Biomolecules
. 2021
;11
(7
):1011
. 14.
Hutchins
NA
, Unsinger
J
, Hotchkiss
RS
, Ayala
A
. The new normal: immunomodulatory agents against sepsis immune suppression
. Trends Mol Med
. 2014
;20
(4
):224
–33
. 15.
Hotchkiss
RS
, Monneret
G
, Payen
D
. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach
. Lancet Infect Dis
. 2013
;13
(3
):260
–8
. 16.
Lu
J
, Chen
R
, Ou
Y
, Jiang
Q
, Wang
L
, Liu
G
, et al. Characterization of immune-related genes andimmune infiltration features for early diagnosis, prognosis and recognition of immunosuppression in sepsis
. Int Immunopharmacol
. 2022
;107
:108650
. 17.
Liu
S
, Li
Y
, She
F
, Zhao
X
, Yao
Y
. Predictive value of immune cell counts and neutrophil-to-lymphocyte ratio for 28-day mortality in patients with sepsis caused by intra-abdominal infection
. Burns Trauma
. 2021
;9
:tkaa040
. 18.
Hu
H
, Sun
SC
. Ubiquitin signaling in immune responses
. Cell Res
. 2016
;26
(4
):457
–83
. 19.
Zhou
Q
, Zhang
J
. K27-linked noncanonic ubiquitination in immune regulation
. J Leukoc Biol
. 2022
;111
(1
):223
–35
. 20.
Popovic
D
, Vucic
D
, Dikic
I
. Ubiquitination in disease pathogenesis and treatment
. Nat Med
. 2014
;20
(11
):1242
–53
. 21.
Liu
T
, Wen
Z
, Shao
L
, Cui
Y
, Tang
X
, Miao
H
, et al. ATF4 knockdown in macrophage impairs glycolysis and mediates immune tolerance by targeting HK2 and HIF-1α ubiquitination in sepsis
. Clin Immunol
. 2023
;254
:109698
. 22.
Shao
S
, Zhou
D
, Feng
J
, Liu
Y
, Baturuhu
YH
, Yin
H
, et al. Regulation of inflammation and immunity in sepsis by E3 ligases
. Front Endocrinol
. 2023
;14
:1124334
. 23.
Srzić
I
, Nesek Adam
V
, Tunjić Pejak
D
. Sepsis definition: what’s new in the treatment guidelines
. Acta Clin Croat
. 2022
;61
(Suppl 1
):67
–72
. 24.
Bhoj
VG
, Chen
ZJ
. Ubiquitylation in innate and adaptive immunity
. Nature
. 2009
;458
(7237
):430
–7
. 25.
Zinngrebe
J
, Montinaro
A
, Peltzer
N
, Walczak
H
. Ubiquitin in the immune system
. EMBO Rep
. 2014
;15
(1
):28
–45
. 26.
Huang
L
, Li
F
, Ye
L
, Yu
F
, Wang
C
. Epigenetic regulation of embryonic ectoderm development in stem cell differentiation and transformation during ontogenesis
. Cell Prolif
. 2023
;56
(4
):e13413
. 27.
Cao
Q
, Wang
X
, Zhao
M
, Yang
R
, Malik
R
, Qiao
Y
, et al. The central role of EED in the orchestration of polycomb group complexes
. Nat Commun
. 2014
;5
:3127
. 28.
Ariës
IM
, Bodaar
K
, Karim
SA
, Chonghaile
TN
, Hinze
L
, Burns
MA
, et al. PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia
. J Exp Med
. 2018
;215
(12
):3094
–114
. 29.
Dong
H
, Liu
S
, Zhang
X
, Chen
S
, Kang
L
, Chen
Y
, et al. An allosteric PRC2 inhibitor targeting EED suppresses tumor progression by modulating the immune response
. Cancer Res
. 2019
;79
(21
):5587
–96
. 30.
Violot
S
, Hong
SS
, Rakotobe
D
, Petit
C
, Gay
B
, Moreau
K
, et al. The human polycomb group EED protein interacts with the integrase of human immunodeficiency virus type 1
. J Virol
. 2003
;77
(23
):12507
–22
. 31.
Wilson
JD
, Hillas
JL
. Astemizole: a new long-acting antihistamine in the treatment of seasonal allergic rhinitis
. Clin Allergy
. 1983
;13
(2
):131
–40
. 32.
Alomar
A
, De La
C
, Fernandez
J
. Cetirizine vs astemizole in the treatment of chronic idiopathic urticaria
. J Int Med Res
. 1990
;18
(5
):358
–65
. 33.
Secchi
AG
. Nedocromil sodium and astemizole, alone or combined, for treatment of seasonal allergic conjunctivitis (SAC)
. Ocul Immunol Inflamm
. 1993
;1
(1–2
):31
–4
. 34.
Poh
AR
, O’Donoghue
RJ
, Ernst
M
. Hematopoietic cell kinase (HCK) as a therapeutic target in immune and cancer cells
. Oncotarget
. 2015
;6
(18
):15752
–71
. 35.
Lei
ST
, Lai
ZZ
, Hou
SH
, Liu
YK
, Li
MQ
, Zhao
D
. Abnormal HCK/glutamine/autophagy axis promotes endometriosis development by impairing macrophage phagocytosis
. Cell Prolif
. 2024
;57
(11
):e13702
. 36.
Liu
Y
, Bezverbnaya
K
, Zhao
T
, Parsons
MJ
, Shi
M
, Treanor
B
, et al. Involvement of the HCK and FGR src-family kinases in FCRL4-mediated immune regulation
. J Immunol
. 2015
;194
(12
):5851
–60
. 37.
Xue
S
, Shi
W
, Shi
T
, Tuerxuntayi
A
, Abulaiti
P
, Liu
Z
, et al. Resveratrol attenuates non-steroidal anti-inflammatory drug-induced intestinal injury in rats in a high-altitude hypoxic environment by modulating the TLR4/NFκB/IκB pathway and gut microbiota composition
. PLoS One
. 2024
;19
(8
):e0305233
. 38.
Yan
Z
, Ji
L
. Hck promotes IL-1β-induced extracellular matrix degradation, inflammation, and apoptosis in osteoarthritis via activation of the JAK-STAT3 signaling pathway
. Adv Rheumatol
. 2024
;64
(1
):88
. 39.
Lowell
CA
, Berton
G
. Resistance to endotoxic shock and reduced neutrophil migration in mice deficient for the Src-family kinases Hck and Fgr
. Proc Natl Acad Sci U S A
. 1998
;95
(13
):7580
–4
. 40.
O’Reilly
LP
, Zhang
X
, Smithgall
TE
. Individual Src-family tyrosine kinases direct the degradation or protection of the clock protein timeless via differential ubiquitylation
. Cell Signal
. 2013
;25
(4
):860
–6
. 41.
Zhang
X
, Cui
Y
, Ding
X
, Liu
S
, Han
B
, Duan
X
, et al. Analysis of mRNA-lncRNA and mRNA-lncRNA-pathway co-expression networks based on WGCNA in developing pediatric sepsis
. Bioengineered
. 2021
;12
(1
):1457
–70
. 42.
Xiao
YP
, Cheng
YC
, Chen
C
, Xue
HM
, Yang
M
, Lin
C
. Identification of the shared gene signatures of HCK, NOG, RNF125 and biological mechanism in pediatric acute lymphoblastic leukaemia and pediatric sepsis
. Mol Biotechnol
. 2025
;67
(1
):80
–90
. 43.
Wang
J
, Lin
Z
, Liu
Q
, Fu
F
, Wang
Z
, Ma
J
, et al. Bat employs a conserved MDA5 gene to trigger antiviral innate immune responses
. Front Immunol
. 2022
;13
:904481
. 44.
Dias Junior
AG
, Sampaio
NG
, Rehwinkel
J
. A balancing act: MDA5 in antiviral immunity and autoinflammation
. Trends Microbiol
. 2019
;27
(1
):75
–85
. 45.
Barrat
FJ
, Elkon
KB
, Fitzgerald
KA
. Importance of nucleic acid recognition in inflammation and autoimmunity
. Annu Rev Med
. 2016
;67
:323
–36
. 46.
Munroe
ME
, Pezant
N
, Brown
MA
, Fife
DA
, Guthridge
JM
, Kelly
JA
, et al. Association of IFIH1 and pro-inflammatory mediators: potential new clues in SLE-associated pathogenesis
. PLoS One
. 2017
;12
(2
):e0171193
. 47.
Luca
D
, Lee
S
, Hirota
K
, Okabe
Y
, Uehori
J
, Izawa
K
, et al. Aberrant RNA sensing in regulatory T cells causes systemic autoimmunity
. Sci Adv
. 2024
;10
(9
):eadk0820
. 48.
Lang
X
, Tang
T
, Jin
T
, Ding
C
, Zhou
R
, Jiang
W
. TRIM65-catalized ubiquitination is essential for MDA5-mediated antiviral innate immunity
. J Exp Med
. 2017
;214
(2
):459
–73
. 49.
Wang
A
, Kang
X
, Wang
J
, Zhang
S
. IFIH1/IRF1/STAT1 promotes sepsis associated inflammatory lung injury via activating macrophage M1 polarization
. Int Immunopharmacol
. 2023
;114
:109478
. 50.
Yang
Z
, Xia
H
, Lai
J
, Qiu
L
, Lin
J
. Artesunate alleviates sepsis-induced liver injury by regulating macrophage polarization via the lncRNA MALAT1/PTBP1/IFIH1 axis
. Diagn Microbiol Infect Dis
. 2024
;110
(1
):116383
. 51.
Simeoni
L
. Lck activation: puzzling the pieces together
. Oncotarget
. 2017
;8
(61
):102761
–2
. 52.
Yang
X
, Hu
B
, Sun
R
, Chen
J
. Deregulation of T cell response in sepsis
. Front Biosci
. 2014
;19
(8
):1370
–6
. 53.
Davies
K
, McLaren
JE
. Destabilisation of T cell-dependent humoral immunity in sepsis
. Clin Sci
. 2024
;138
(1
):65
–85
. 54.
Al-Harbi
NO
, Ahmad
SF
, Almutairi
M
, Alanazi
AZ
, Ibrahim
KE
, Alqarni
SA
, et al. Lck signaling inhibition causes improvement in clinical features of psoriatic inflammation through reduction in inflammatory cytokines in CD4+ T cells in imiquimod mouse model
. Cell Immunol
. 2022
;376
:104531
. 55.
Shih
YC
, Chen
HF
, Wu
CY
, Ciou
YR
, Wang
CW
, Chuang
HC
, et al. The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling
. Nat Commun
. 2024
;15
(1
):532
. 56.
Rao
N
, Miyake
S
, Reddi
AL
, Douillard
P
, Ghosh
AK
, Dodge
IL
, et al. Negative regulation of Lck by Cbl ubiquitin ligase
. Proc Natl Acad Sci U S A
. 2002
;99
(6
):3794
–9
. 57.
Chen
M
, Chen
X
, Hu
Y
, Cai
X
. Screening of key genes related to the prognosis of mouse sepsis
. Biosci Rep
. 2020
;40
(10
). 58.
Almansa
R
, Heredia-Rodríguez
M
, Gomez-Sanchez
E
, Andaluz-Ojeda
D
, Iglesias
V
, Rico
L
, et al. Transcriptomic correlates of organ failure extent in sepsis
. J Infect
. 2015
;70
(5
):445
–56
. 59.
Kong
F
, Zhu
Y
, Xu
J
, Ling
B
, Wang
C
, Ji
J
, et al. The novel role of LCK and other PcDEGs in the diagnosis and prognosis of sepsis: insights from bioinformatic identification and experimental validation
. Int Immunopharmacol
. 2025
;149
:114194
. 60.
Jiang
Y
, Miao
Q
, Hu
L
, Zhou
T
, Hu
Y
, Tian
Y
. FYN and CD247: key genes for septic shock based on bioinformatics and meta-analysis
. Comb Chem High Throughput Screen
. 2022
;25
(10
):1722
–30
. 61.
Xie
K
, Wang
F
, Yang
Y
, Pan
S
, Wang
J
, Xiao
N
, et al. Monotropein alleviates septic acute liver injury by restricting oxidative stress, inflammation, and apoptosis via the AKT (Ser473)/GSK3β (Ser9)/Fyn/NRF2 pathway
. Int Immunopharmacol
. 2024
;142
(Pt B
):113178
. 62.
Xie
D
, Shen
F
, He
S
, Chen
M
, Han
Q
, Fang
M
, et al. IL-1β induces hypomyelination in the periventricular white matter through inhibition of oligodendrocyte progenitor cell maturation via FYN/MEK/ERK signaling pathway in septic neonatal rats
. Glia
. 2016
;64
(4
):583
–602
. 63.
Unal
U
, Comertpay
B
, Demirtas
TY
, Gov
E
. Drug repurposing for rheumatoid arthritis: identification of new drug candidates via bioinformatics and text mining analysis
. Autoimmunity
. 2022
;55
(3
):147
–56
. 64.
Hörner
C
, Bouchon
A
, Bierhaus
A
, Nawroth
PP
, Martin
E
, Bardenheuer
HJ
, et al. Role of the innate immune response in sepsis
. Anaesthesist
. 2004
;53
(1
):10
–28
. 65.
Pinheiro da Silva
F
, Aloulou
M
, Skurnik
D
, Benhamou
M
, Andremont
A
, Velasco
IT
, et al. CD16 promotes Escherichia coli sepsis through an FcR gamma inhibitory pathway that prevents phagocytosis and facilitates inflammation
. Nat Med
. 2007
;13
(11
):1368
–74
. 66.
Zhang
W
, Chen
L
, Lu
X
, Dong
X
, Feng
M
, Tu
Y
, et al. EFHD2 regulates T cell receptor signaling and modulates T helper cell activation in early sepsis
. Int Immunopharmacol
. 2024
;133
:112087
. 67.
Huang
S
, Liu
D
, Sun
J
, Zhang
H
, Zhang
J
, Wang
Q
, et al. Tim-3 regulates sepsis-induced immunosuppression by inhibiting the NF-κB signaling pathway in CD4 T cells
. Mol Ther
. 2022
;30
(3
):1227
–38
. 68.
Halstead
ES
, Carcillo
JA
, Schilling
B
, Greiner
RJ
, Whiteside
TL
. Reduced frequency of CD56 dim CD16 pos natural killer cells in pediatric systemic inflammatory response syndrome/sepsis patients
. Pediatr Res
. 2013
;74
(4
):427
–32
. 69.
Zhang
X
, Zhang
Y
, Yuan
S
, Zhang
J
. The potential immunological mechanisms of sepsis
. Front Immunol
. 2024
;15
:1434688
. 70.
Córneo
EDS
, Michels
M
, Dal-Pizzol
F
. Sepsis, immunosuppression and the role of epigenetic mechanisms
. Expert Rev Clin Immunol
. 2021
;17
(2
):169
–76
. 71.
Danahy
DB
, Strother
RK
, Badovinac
VP
, Griffith
TS
. Clinical and experimental sepsis impairs CD8 T-Cell-Mediated immunity
. Crit Rev Immunol
. 2016
;36
(1
):57
–74
. 72.
Li
LL
, Dai
B
, Sun
YH
, Zhang
TT
. Monocytes undergo functional reprogramming to generate immunosuppression through HIF-1α signaling pathway in the late phase of sepsis
. Mediators Inflamm
. 2020
;2020
:4235909
. © 2025 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2025
You do not currently have access to this content.
