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Microbes & Immunity PTMs in Sepsis: Mechanisms and therapy

phosphorylation, exacerbating renal tubular epithelial therapeutic targets, while colchicine, pectolinarigenin,
cell pyroptosis, while the endogenous regulator Wild- 4-octyl itaconate, and mesenchymal stem cells show
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type p53-induced phosphatase 1 (WIP1) exerts a negative promise as STAT3-targeting agents in sepsis management.
regulatory effect by dephosphorylating p38 MAPK,
alleviating pyroptosis-related kidney injury. 48 3.4. PI3K/AKT signaling pathway

Thus, targeting the MAPK pathway offers promising The PI3K/AKT pathway is a vital intracellular signaling
avenues for suppressing inflammation and balancing network wherein phosphatidylinositol 3-kinase (PI3K)
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immune responses. Its interactions with NF-κB, activates AKT through phosphorylation. Activated AKT
the NLRP3 inflammasome, and cell death pathways regulates inflammation, oxidative stress, and apoptosis by
demonstrate its potential in treating sepsis. Molecules influencing downstream effectors. 59
such as ADM2, MaR1, peptidyl-prolyl cis/trans isomerase Targeted modulation of the PI3K/AKT pathway can
(Pin1), WIP1, and TLR4 provide opportunities for precise mitigate sepsis-induced organ damage by balancing
intervention by modulating MAPK phosphorylation. inflammation and tissue repair. Blocking hepatocyte
Natural products and synthetic compounds, including growth factor binding to c-Met inhibits PI3K/AKT
THC, PVB, artesunate, and fisetin, exhibit therapeutic phosphorylation, reducing oxidative stress, pro-
potential by improving organ function and survival rates inflammatory cytokine production (e.g., IL-6), and
through multi-target effects. cardiomyocyte apoptosis in early sepsis, though
prolonged inhibition may impair tissue regeneration. 60,61
3.3. Signal transducer and activator of transcription Alternatively, inhibiting sphingosine 1-phosphate lyase
3 (STAT3) signaling pathway
(S1P) and activating S1P receptor type 3 suppress AKT
STAT3, a member of the STAT protein family, is a central phosphorylation, preserving lung and kidney microvascular
transcription factor in immune and inflammatory barriers and reducing systemic inflammation, offering
signaling. 49 Following phosphorylation, STAT3 potential for antibiotic-resistant cases. AKT-driven
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translocates to the nucleus, driving transcription of NF-κB phosphorylation amplifies pro-inflammatory
genes involved in inflammation, cell proliferation, cascades, but compounds such as annexin A1 (Ac2-26)
differentiation, and apoptosis during the acute phase of and hibifolin inhibit NF-κB, protecting against renal
sepsis, thereby modulating immune responses and multi- and lung injury. 63-65 In contrast, the traditional Chinese
organ dysfunction. 50,51 medicine compound Xuebijing (XBJ) activates AKT
Colchicine inhibits NLRP3 inflammasome activation phosphorylation by increasing vascular endothelial growth
by suppressing STAT3 phosphorylation, reducing factor A expression to improve intestinal microcirculation
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inflammation, pyroptosis, and oxidative stress in sepsis- in sepsis. Similarly, phenylpropylene (BNP) exerts anti-
induced ALI. Conversely, phospholipase D2 (PLD2) inflammatory effects by inducing AKT phosphorylation
52
enhances STAT3 phosphorylation through phospholipid and reducing IL-6 expression. 67
acid, negatively regulating tight junction protein The dual role of the PI3K/AKT pathway in sepsis
expression in pulmonary vascular endothelium and – both protective and detrimental – complicates its
exacerbating ALI. In sepsis-associated AKI, Lyn (a Src therapeutic application. Nevertheless, hibifolin, XBJ, and
53
family kinase) and pectolinarigenin (a flavonoid) suppress phenpropylline merit further exploration as potential
STAT3 phosphorylation, inhibiting inflammatory sepsis treatments.
factor release and reducing renal cell apoptosis, thus
protecting against AKI. 54,55 In addition, 4-octyl itaconate, 4. Ubiquitination and sepsis
a multi-target itaconate derivative, suppresses STAT3 Ubiquitination, mediated by E1-E2-E3 cascades, critically
phosphorylation to mitigate renal inflammation and regulates immune responses and cell death in sepsis. This
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oxidative stress while promoting mitophagy and process involves the attachment of ubiquitin, a 76-amino
cell homeostasis. Mesenchymal stem cells regulate acid protein with seven lysine residues (K6, K11, K27, K29,
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inflammatory response by inhibiting both STAT1 and K33, K48, K63), to substrate proteins, forming monomeric,
STAT3 phosphorylation, modulating T helper (Th) cell branched and linear chains. E3 ubiquitin ligases,
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subset numbers and functions, reducing organ damage, categorized into RING, HECT, and RBR families, confer
and improving survival in septic models. 57 substrate specificity. Ubiquitination modification plays a
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The pivotal role of STAT3 in sepsis highlights the need key role in modulating NLRP3 inflammasome activation
to develop therapies that downregulate its signaling. Newly and programmed cell death pathways, influencing sepsis
identified regulators such as PLD2 and Lyn offer novel pathogenesis.

Volume 2 Issue 3 (2025) 4 doi: 10.36922/MI025090016