Sepsis is a complex disorder characterized by a dysregulated immune response to infection. Elevated lactic acid levels and lactylation modification may induce changes in gene expression and immune cell infiltration in sepsis.
Methods
RNA-seq data and clinical information related to sepsis were obtained from GEO datasets. Differential expression analysis identified genes that are differentially expressed between sepsis patients and healthy controls. The lactylation-related genes were then integrated with the differential expressed genes to classify genes as Sepsis-related differentially expressed lactylation-related genes (Sepsis-DELRGs). Mendelian randomization analysis was performed to assess the causal relationship between Sepsis-DELRGs and the two groups. Machine learning algorithms predicted potential Sepsis-DELRGs, and immune infiltration analysis examined the relationships between these genes and immune cell types. Finally, we examined the expression of MDC1 and LYRM4 within the GSE131761 and GSE80496 datasets and in sepsis patients from our hospital.
Results
A total of 1356 differentially expressed genes were identified between sepsis patients and healthy controls. From these, 138 Sepsis-DELRGs associated with sepsis were isolated. Mendelian randomization identified LYRM4 and MDC1 as protective factors against sepsis. Both genes positively influence CD8+ T cells and negatively affect activated mast cells and neutrophils. The expression levels of LYRM4 and MDC1 in CD8+ T cells from sepsis patients were low. ROC curve analysis demonstrated that both genes have strong predictive power for sepsis onset.
Conclusions
LYRM4 and MDC1 could serve as potential biomarkers for differentiating sepsis patients from healthy individuals. Their functions are closely linked to changes in inflammatory cell populations in sepsis.
MeyerNJPrescottHC. Sepsis and septic shock. New Engl J Med. 2024;391:2133-2146. doi:10.1056/NEJMra2403213
2.
Fleischmann-StruzekCMellhammarLRoseN, et al.Incidence and mortality of hospital- and icu-treated sepsis: Results from an updated and expanded systematic review and meta-analysis. Intens Care Med. 2020;46:1552-1562. doi:10.1007/s00134-020-06151-x
3.
YouSBSongJHsuJYBowlesKH. Characteristics and readmission risks following sepsis discharges to home. Med Care. 2025;63:89-97. doi:10.1097/MLR.0000000000002091
4.
NanahAAbdeljaleelFGarciaM, et al.Sepsis survivors readmitted within 30 days: Outcomes of a single-center retrospective study. Crit Care Sci. 2024;36:e20240116e.
5.
ZhangTChenLKuethG, et al.Lactate's impact on immune cells in sepsis: Unraveling the complex interplay. Front Immunol. 2024;15:1483400. doi:10.3389/fimmu.2024.1483400
6.
LiuSYangTJiangQ, et al.Lactate and lactylation in sepsis: A comprehensive review. J Inflamm Res. 2024;17:4405-4417. doi:10.2147/JIR.S459185
7.
JosephPADoluweeraDChandraratneA, et al.Capillary lactate as a prognostic marker in sepsis: Correlation with venous lactate and prediction of outcomes. Bmc Infect Dis. 2025;25:438. doi:10.1186/s12879-025-10810-z
8.
ChenSQinTLuoS, et al.Lactylation and viral infections: A novel link between metabolic reprogramming and immune regulation. Plos Pathog. 2025;21:e1013366. doi:10.1371/journal.ppat.1013366
9.
ZhangDTangZHuangH, et al.Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574:575-580. doi:10.1038/s41586-019-1678-1
10.
ShiCOuXHuangL, et al.Integrating geo database, Mendelian randomization, and molecular docking to identify hla-c as a potential therapeutic target for periodontitis. Mediat Inflamm. 2025;2025:9163431. doi:10.1155/mi/9163431
11.
SunPFengSYuHWangXFangY. Two hub genes of bipolar disorder, a bioinformatics study based on the geo database. Ibro Neurosci Rep. 2024;17:122-130. doi:10.1016/j.ibneur.2024.07.006
12.
ChengZHuangHLiMLiangXTanYChenY. Lactylation-related gene signature effectively predicts prognosis and treatment responsiveness in hepatocellular carcinoma. Pharmaceuticals-Base. 2023;16:644. doi:10.3390/ph16050644
13.
SunCZhangWLiuH, et al.Identification of a novel lactylation-related gene signature predicts the prognosis of multiple myeloma and experiment verification. Sci Rep-UK. 2024;14:15142. doi:10.1038/s41598-024-65937-x
14.
HuangHChenKZhuY, et al.A multi-dimensional approach to unravel the intricacies of lactylation related signature for prognostic and therapeutic insight in colorectal cancer. J Transl Med. 2024;22:211. doi:10.1186/s12967-024-04955-9
15.
PengTSunFYangJC, et al.Novel lactylation-related signature to predict prognosis for pancreatic adenocarcinoma. World J Gastroentero. 2024;30:2575-2602. doi:10.3748/wjg.v30.i19.2575
16.
ZhangLLiBLiuJBianYFLinGXZhouY. Unveiling hub genes and biological pathways: A bioinformatics analysis of trauma-induced coagulopathy (tic). Plos One. 2025;20:e322043.
17.
LiLGuoHZhangW, et al.Biomarker identification for rheumatoid arthritis with inadequate response to dmard and tnf therapies using multidimensional analyses. Immunobiology. 2025;230:152901. doi:10.1016/j.imbio.2025.152901
18.
ZhengYYangYXiongQMaYZhuQ. Establishment and verification of a novel gene signature connecting hypoxia and lactylation for predicting prognosis and immunotherapy of pancreatic ductal adenocarcinoma patients by integrating multi-machine learning and single-cell analysis. Int J Mol Sci. 2024;25:11143. doi: 10.3390/ijms252011143
19.
YanLDongZChenYHanYTongC. Comprehensive analysis of lymphocyte subsets and transcriptome profiles in sepsis-induced acute respiratory distress syndrome: A prospective, observational study. Clinics. 2025;80:100754. doi:10.1016/j.clinsp.2025.100754
20.
YanLChenYYangYHanYTongC. Heat shock protein 90α reduces cd8(+) t cell exhaustion in acute lung injury induced by lipopolysaccharide. Cell Death Discov. 2024;10:283. doi:10.1038/s41420-024-02046-8
21.
Moncada-GutiérrezDVásquez-TiradoGAMeregildo-RodríguezED, et al.Lactate-enhanced-qsofa (lqsofa) score as a predictor of in-hospital mortality in patients with sepsis: Systematic review and meta-analysis. Eur J Trauma Emerg S. 2025;51:33. doi:10.1007/s00068-024-02757-8
22.
MaFYuW. The roles of lactate and lactylation in diseases related to mitochondrial dysfunction. Int J Mol Sci. 2025;26:7149. doi: 10.3390/ijms26157149
23.
GhadyaniFZandiPGhafouri-FardS. Histone lactylation: A new target for overcoming immune evasion and therapy resistance. Med Oncol. 2025;42:399. doi:10.1007/s12032-025-02940-w
24.
YangKFanMWangX, et al.Lactate promotes macrophage hmgb1 lactylation, acetylation, and exosomal release in polymicrobial sepsis. Cell Death Differ. 2022;29:133-146. doi:10.1038/s41418-021-00841-9
25.
HaoZNTanXPZhangQLiJXiaRMaZ. Lactate and lactylation: Dual regulators of t-cell-mediated tumor immunity and immunotherapy. Biomolecules. 2024;14:1646. doi:10.3390/biom14121646
26.
LuZFangPLiS, et al.Lactylation of histone h3k18 and egr1 promotes endothelial glycocalyx degradation in sepsis-induced acute lung injury. Adv Sci. 2025;12:e2407064. doi:10.1002/advs.202407064
27.
SunZSongYLiJLiYYuYWangX. Potential biomarker for diagnosis and therapy of sepsis: Lactylation. Immun Inflamm Dis. 2023;11:e1042. doi:10.1002/iid3.1042
28.
LiuYCaoY. Mediating role of blood metabolites in the relationship between immune cell traits and sepsis: A Mendelian randomization and mediation analysis. Inflamm Res. 2025;74:5. doi:10.1007/s00011-024-01971-9
29.
QuJZhangL. The gut microbiome and ovarian cysts: A Mendelian randomization study. J Ovarian Res. 2025;18:188. doi:10.1186/s13048-025-01767-3
30.
ZhengYNQiuPLuoHHChenRJWangXQChenPJ. Association of pulmonary function with the risk of incident Alzheimer's disease: A prospective cohort and Mendelian randomization study. Aging Clin Exp Res. 2025;37:244. doi:10.1007/s40520-025-03151-z
31.
SunJWuYBurgessSWengYWangZ. Mitochondrial-related genome-wide Mendelian randomization identifies putatively causal genes in the pathogenesis of sepsis. Surgery. 2025;181:109150. doi:10.1016/j.surg.2025.109150
32.
LiuXWangYTanC, et al.Novel variants in mdc1 were associated with severe oligoasthenoteratozoospermia. Clin Genet. 2025;109:552-557.doi: 10.1111/cge.70058
33.
TorresEMStewartMJBraggintonE, et al.Mdc1 mediates pellino recruitment to sites of dna double-strand breaks. Life Sci Alliance. 2025;8:e202403074.doi: 10.26508/lsa.202403074
34.
CaiJSongLZhangF, et al.Targeting srsf10 might inhibit m2 macrophage polarization and potentiate anti-pd-1 therapy in hepatocellular carcinoma. Cancer Commun. 2024;44:1231-1260. doi:10.1002/cac2.12607
35.
YanLChenYHanYTongC. Role of cd8(+) t cell exhaustion in the progression and prognosis of acute respiratory distress syndrome induced by sepsis: A prospective observational study. Bmc Emerg Med. 2022;22:182. doi:10.1186/s12873-022-00733-2
36.
WangZHZhaoYZhangL. Emerging trends and hot topics in the application of multi-omics in drug discovery: A bibliometric and visualized study. Curr Pharm Anal. 2024;21:20-32. doi:10.1016/j.cpan.2024.12.001
