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Microbes & Immunity PTMs in Sepsis: Mechanisms and therapy

7. Lactylation and sepsis protein function, are implicated in sepsis pathogenesis,
offering potential therapeutic targets. 112
Lactylation, the addition of lactyl groups to lysine residues,
represents another PTM implicated in sepsis. In This review summarizes the potential role of PTMs
103
sepsis, increased glycolysis leads to lactate accumulation, in sepsis and sepsis-induced multiple organ dysfunction
driving both histone and non-histone lactylation, thereby identified in recent years (Figure 1 and Table 1).
dynamically controlling gene expression and contributing Phosphorylation, ubiquitination, and SUMOylation
to organ dysfunction. 104 primarily contribute to the early inflammatory storm, with
NF-κB, MAPK, and STAT3 phosphorylation driving pro-
7.1. Histone lactylation inflammatory cytokine release, and E3 ligase regulating
Histone H3 lysine 18 lactylation (H3K18la), a specific NLRP3 inflammasome activation and cell death. The PI3K/
lactylation site, promotes METTL3 expression and AKT pathway exhibits dual role in sepsis. XBJ improves
transcription factor early growth response protein 1 intestinal microcirculation by activating the PI3K/AKT
66
(EGR1) enrichment, exacerbating ALI in sepsis. 105,106 pathway, while hibifolin inhibits this pathway to alleviate
65
Lactate-induced H3K18la activates RhoA protein and lung injury, highlighting the need for tissue-specific
mediates downstream inflammation and apoptosis, regulation. Acetylation and lactylation are dynamically
leading to kidney injury. It also activates ezrin K263 regulated by metabolites (acetyl-CoA, lactate), forming
a “metabolism–PTM-gene expression” cascade. SIRT3
lactylation, identifying ezrin as a lactate substrate for the downregulation-mediated PDHA1 acetylation induces
1 time. Lactate also increases H3K14la levels, activating Fis1 lactylation, suggesting that targeting metabolic
st
107
inflammation of endothelial cells and lung injury by enzymes may regulate multiple PTMs simultaneously.
21
promoting transcription of ferroptosis-related genes Furthermore, NAD+ precursor NMN inhibits NF-κB
TFRC and SLC40A1. These findings suggest histone by activating SIRT1, providing a strategy for combined
108
lactylation as a regulator of sepsis-induced organ damage, metabolic and immune regulation. 97
with METTL3 and EGR1 represents promising therapeutic
targets. However, most studies are limited to single PTM or
organ, lacking systematic analysis of multi-modification
7.2. Non-histone lactylation interactions like ubiquitination-acetylation competition,
While initially identified on histones, non-histone and systemic effects. Tissue-specific E3 ligase distribution,
lactylation is also a focus of current research. Lactate such as the opposing effects of TRIM21 in lung epithelium
promotes HMGB1 lactylation and acetylation through versus TRIM31 in myocardium, highlights the need
a p300/CBP-dependent pathway, leading to its release for organ-targeted delivery systems, reducing off-target
and endothelial barrier dysfunction, promoting sepsis toxicity. 85,113 Future studies can focus on developing dual-
development. In addition, lactate mediates mitochondrial function molecules such as inhibiting phosphorylation
109
fission 1 protein lysine 20 (Fis1 K20la) lactylation, and activating deacetylation, synergistically regulating
promoting excessive mitochondrial fission and exacerbating immune balance, or combining PTM inhibitors with drugs
sepsis-induced AKI. Notably, this process is driven by targeting various mechanisms to improve sepsis treatment
SIRT3 downregulation-mediated hyperacetylation and efficacy.
inactivation of pyruvate dehydrogenase E1 component In conclusion, exploring PTMs-related regulatory
subunit α (PDHA1), leading to lactate excess in factors offers a novel strategy for developing sepsis
21
endothelial cells of renal tubules. The interplay between therapeutics. However, translation to clinical application
lactylation and acetylation, driven by lactate and acetyl- requires further investigation to shift sepsis treatment
CoA, respectively, highlights the importance of metabolic from “broad-spectrum anti-inflammation” to “precise
homeostasis in sepsis. Targeting HMGB1 and PDHA1 modification and regulation.”
110
may offer novel therapeutic strategies by modulating the
dynamic homeostasis between acetylation and lactylation. Acknowledgments
None.
8. Conclusion and perspectives
Sepsis pathogenesis involves an initial hyperinflammation Funding
phase driven by excessive inflammatory cytokines release, This work was supported by the Beijing Natural Science
followed by immunosuppression characterized by anti- Foundation (grant number: L246039), the National
inflammatory cytokine production, immune cell death, and Natural Science Foundation of China (grant numbers:
regulatory cell proliferation. PTMs, critical regulators of 82372189, 81871586, and 82172128), and the Beijing High-
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Volume 2 Issue 3 (2025) 8 doi: 10.36922/MI025090016