Sepsis Treatments Shift Toward Precision, Multi-System Pharmacology

Sepsis pharmacology is moving beyond the idea that the condition is simply a systemic cytokine storm, according to an editorial examining 21 contributions to a research collection on inflammatory pathways, oxidative stress, mitochondrial injury, vascular dysfunction, and metabolic changes. The authors argue that the next generation of treatments will need to identify the biological phenotype of each patient, select an intervention that matches the dominant abnormality, and adapt that intervention to the stage of illness. The collection includes experimental studies, systematic reviews, network meta-analysis, real-world evidence, and randomized clinical research, but the editorial stresses that no single approach yet resolves the complexity of sepsis.

Sepsis continues to carry a high mortality burden despite advances in antimicrobial therapy, source control, hemodynamic resuscitation, and organ support. Its biological course involves not only excessive inflammation but also changes in immune regulation, oxidative balance, mitochondrial function, endothelial integrity, metabolism, coagulation, and organ homeostasis. Innate immune receptor activation can engage NF-κB, MAPK, inflammasome, and related pathways, leading to mediators such as TNF-α, IL-1β, IL-6, and HMGB1. Yet these signals operate within an interconnected network, making it difficult to expect consistent benefit from suppressing one cytokine alone.

Mitochondrial dysfunction is one of the central links in that network. Impaired oxidative phosphorylation, excessive reactive oxygen species, ATP depletion, and mitochondrial damage can intensify inflammatory signaling and cellular injury, while the resulting tissue stress can further disrupt mitochondrial function. The editorial therefore treats mitochondrial quality control—including biogenesis, dynamics, and mitophagy—as a possible therapeutic target rather than a secondary feature of sepsis. Experimental work on Xiangdan injection reported attenuation of inflammatory responses and cardiac injury together with mitochondrial protection in an experimental sepsis model. However, many preclinical studies define mitochondrial protection through morphology or selected protein markers rather than direct measurements of respiration, ATP production, membrane potential, mitophagy flux, or biogenesis. The decisive question is therefore not only whether a treatment lowers oxidative-stress markers, but whether it restores cellular bioenergetic function.

Another strand of the collection focuses on the vascular consequences of immune activation. Neutrophil extracellular traps, or NETs, can contribute to endothelial damage, coagulation activation, increased vascular permeability, immunothrombosis, and impaired microcirculation. Because organ injury depends on perfusion, oxygen delivery, and microvascular blood flow as well as cytokine concentrations, therapies that modify interactions between inflammatory cells and the vasculature may complement direct cytokine inhibition. In experimental sepsis, docosahexaenoic acid was associated with reduced inflammatory responses, neutrophil adhesion, and microcirculatory abnormalities. The same study reported increased formation of pro-resolving mediators, but that measurement used enzyme immunoassays with limited selectivity in complex biological samples; the authors therefore say the result requires confirmation by LC-MS/MS. They also argue that future NET-directed studies should test whether such treatments improve organ perfusion and clinical outcomes without weakening antimicrobial host defense.

The editorial also highlights a central problem with the cytokine-storm framework: hyperinflammation and immunosuppression can coexist, and a patient may move from one state to another during the course of illness. A systematic review and network meta-analysis in the collection synthesized 76 randomized trials involving 22,194 patients and assessed several immunomodulatory interventions. Ulinastatin, ulinastatin combined with thymosin-α1, and polyunsaturated fatty acids showed potential benefits, but heterogeneity and limitations in the certainty of the evidence temper those results. The relevant clinical question may thus be not whether inflammation should always be suppressed, but which biological phenotype requires treatment and when. Patients dominated by hyperinflammation may be biologically distinct from those with impaired immune competence, and treating both as a single syndrome could produce inconsistent results.

Metabolic and cardiovascular pharmacology broadens the potential toolkit beyond conventional anti-inflammatory agents. In a randomized controlled study of patients with septic shock, anisodamine hydrobromide was associated with lower 28-day mortality, with lactate-related variables contributing to the observed effect. The result is consistent with the possibility that improving microcirculation and tissue perfusion may be therapeutically important, although the editorial does not present the study as definitive evidence for routine use. A study of the GLP-1 receptor agonist liraglutide during sepsis reported effects on retinal endothelial function and oxidative stress, indicating that metabolic signaling may influence vascular injury during systemic inflammation. In a separate real-world cohort of patients with diabetic kidney disease, finerenone was associated with lower risks of sepsis-induced cardiomyopathy and mortality than steroidal mineralocorticoid receptor antagonists. Because that finding was observational, it cannot establish causality, but it supports prospective evaluation of drugs whose host-directed effects may extend beyond their original indications.

Natural products and drug repurposing form a substantial part of the research collection, which included work on artesunate, Dachengqi Decoction, Xiangdan injection, sophoridine, ganoderic acid A, Handelin, and docosahexaenoic acid. Their potential advantage is multitarget activity across inflammatory, oxidative, mitochondrial, metabolic, and cell-death pathways, all of which contribute to sepsis. The same complexity creates translational obstacles: variable composition, uncertain bioavailability, poorly characterized pharmacokinetics, difficulty achieving clinically relevant concentrations, and limited randomized evidence. Some work is beginning to move beyond pathway association. Multi-omics combined with experimental validation identified TNF-α as a candidate target in sepsis-related liver injury in a ganoderic acid A study, while proteomic profiling of Handelin nominated the proteasome subunits PSMA7 and PSMB2 as possible targets in the regulation of proteostasis. A separate study integrated metabolomics, drug-metabolism and pharmacokinetic analysis, network pharmacology, molecular modeling, cellular experiments, and animal work to investigate artesunate-induced nephrotoxicity. That model does not directly demonstrate sepsis efficacy, an important distinction the editorial emphasizes.

Evidence for artesunate itself was more directly related to sepsis in a systematic review and meta-analysis of animal studies, which reported beneficial effects on survival and inflammatory or organ-injury outcomes. The authors nevertheless note heterogeneity and limitations in the preclinical evidence. The broader lesson is that candidate interventions need to progress from associations in omics or pathway analyses to validated molecular targets, measurable exposure, target engagement, functional efficacy, and eventual clinical testing. This applies particularly to combination therapy. Combining agents merely because they act through different mechanisms is less persuasive than selecting combinations that correct complementary abnormalities in patients whose biology supports that strategy.

Organ-specific toxicity and precision dosing add another dimension to sepsis pharmacology. Among patients with sepsis, higher vancomycin concentrations were associated with increased risk of acute kidney injury, and hyperlactatemia modified that relationship. The finding indicates that the same drug exposure may have different effects depending on a patient’s physiological state. A systematic review comparing vasopressin with norepinephrine found potential renal advantages for vasopressin, including lower serum creatinine and reduced renal-replacement therapy, although effects on acute kidney injury were less consistent. Such findings reinforce that advances in sepsis treatment require not only new drugs but also better optimization of existing medicines according to organ function, metabolic condition, infection characteristics, and measured exposure.

Several gaps remain before this precision approach can be applied reliably. Trials have not yet incorporated biological heterogeneity enough to identify which patients are most likely to benefit from particular interventions. Biomarkers of inflammation, immune competence, endothelial injury, mitochondrial dysfunction, and metabolism may eventually help classify patients, while the timing of treatment is likely to matter because an intervention that helps during early hyperinflammation may be ineffective or harmful during later immunosuppression. Mechanistic claims also require stronger validation than molecular docking, transcriptomic associations, or pathway enrichment; target engagement, genetic manipulation, rescue experiments, and functional assays provide more direct causal evidence. Preclinical models should better represent differences in age, sex, diabetes, obesity, chronic kidney disease, immunosuppression, infection characteristics, antibiotics, fluid resuscitation, and vasopressor use. The editorial’s conclusion is not that a universal anti-inflammatory drug is unnecessary, but that broader suppression should give way to interventions selected for the right biological phenotype at the right time. By integrating immune phenotyping with mitochondrial, vascular, metabolic, pharmacokinetic, and organ-specific information, sepsis therapy may become better able to interrupt self-amplifying injury while preserving antimicrobial defense.

Subject of Research: Precision pharmacological treatment of sepsis across inflammatory, mitochondrial, vascular, and metabolic pathways

Article Title: Editorial: Pharmacological modulation of inflammatory pathways in sepsis: targeting the cytokine storm and septic oxidative stress

Article References: Zhang, G., VanBramer, H., Wang, D., Prasad, A., & Meng, Q. (2026). Editorial: Pharmacological modulation of inflammatory pathways in sepsis: targeting the cytokine storm and septic oxidative stress. Frontiers in Pharmacology, 17, Article 2021242. https://doi.org/10.3389/fphar.2026.2021242

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.2021242

Keywords: sepsis, cytokine storm, oxidative stress, mitochondrial dysfunction, immunomodulation, microcirculation, natural products, precision medicine, drug repurposing, Editorial, Pharmacological, modulation