Sepsis is a life-threatening clinical syndrome resulting from a dysregulated host response to infection, leading to widespread inflammation, tissue damage, and multi-organ failure (Cao et al., 2023; Baddam and Burns, 2025). Despite major advances in antibiotic therapy, hemodynamic support, and critical care technologies, the mortality rate associated with sepsis remains unacceptably high, ranging from 25% to 40% in intensive care units (ICUs) worldwide (Waxman et al., 2005; La Via et al., 2025). Current therapeutic interventions primarily aim to eradicate infection and maintain organ function through modalities such as mechanical ventilation (MV), continuous renal replacement therapy (CRRT), and vasopressor administration—most commonly norepinephrine (NE) to sustain blood pressure (La Via et al., 2025). However, these approaches offer limited impact on the underlying immunopathology of sepsis, which is characterized by uncontrolled inflammation, immune exhaustion, and metabolic dysregulation. Conventional immunomodulatory therapies including corticosteroids, cytokine antagonists, complement or coagulation regulators, and intravenous immunoglobulins have demonstrated inconsistent or modest benefits, emphasizing the need for alternative host-directed therapeutic strategies that can modulate immune responses rather than merely suppress infection (Jain et al., 2024). Omega-3 fatty acids (Ω-3 FAs), a subclass of polyunsaturated fatty acids (PUFAs), have gained increasing attention for their anti-inflammatory and immunoresolving properties (Jerab et al., 2025). These bioactive lipids are precursors of specialized pro-resolving mediators such as resolving, protections, and margins, which actively terminate inflammation, enhance macrophage-mediated clearance, and promote tissue repair. Experimental and clinical studies have suggested that Ω-3 FA supplementation may improve immune homeostasis, reduce pro-inflammatory cytokine release, and attenuate organ injury in sepsis. For instance, a pilot randomized trial in septic patients with intestinal dysfunction found that fish-oil–based Ω-3 supplementation improved T helper/inducer and CD4/CD8 lymphocyte ratios and reduced 28-day mortality (12.5% vs 41.7%) compared with standard care (Jerab et al., 2025). Nevertheless, the therapeutic efficacy of Ω-3 FAs in sepsis remains controversial. Meta-analyses of randomized controlled trials have shown conflicting results: an earlier analysis of 17 RCTs (1239 patients) reported a non-significant mortality benefit (RR ≈ 0.85, 95% CI 0.71–1.03) but reduction in ICU-length of stay and duration of mechanical ventilation (Lu et al., 2017). A more recent meta-analysis of 20 RCTs (1514 patients) found a significant association between Ω-3 supplementation and reduced mortality (RR = 0.82, 95% CI 0.69–0.97) especially in patients with gastrointestinal dysfunction (Wang et al., 2020; Li et al., 2024). Importantly, evidence derived from randomized trials may not fully capture the complexity of routine clinical practice. Real-world studies provide a valuable complement by reflecting heterogeneous patient populations, treatment variations, and dynamic clinical decision-making. Therefore, this retrospective real-world study was designed to evaluate the impact of Ω-3 FA supplementation on ICU mortality in patients with sepsis. The findings aim to generate clinically meaningful evidence on the host-directed immunomodulatory role of Ω-3 FAs and support their potential development as adjunct therapeutic agents for systemic inflammatory and infection-associated disorders.

The study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and complied with relevant Chinese regulations. And the study was authorized by the Medical Department of Shenzhen People’s Hospital and approved by the hospital’s Ethics Committee, with the serial number LL-KY-2023207-01. The Ethics Committee granted exemption from obtaining signed informed consent forms for this study. Patient information was obtained through the hospital’s information system for retrospective real-world. The research was conducted in the critical care department of the hospital, which had a capacity of 22 beds.

From December 2016 to July 2019, a total of 1997 patients were admitted to the Department of Intensive Care Medicine at Shenzhen People’s Hospital. Among them, according to inclusion criteria and exclusion criteria, 1733 patients were included in the study. Of these patients, 1013 patients were male and 720 patients were female, with an average age of 61.76 years old,382 patients died, resulting in a mortality rate of 22.04% (refer to Supplementary Table 1). 492 patients with missing microbiological test were excluded, and 1241 patients included in the study. Matching was per-formed with the use of 1:2, a total of 633 patients were obtained. Among these, 211 cases were in the treatment group with Omega-3 fatty acid, and 422 cases were in the control group. The patient enrolment was illustrated in Figure 1 comparative analysis of patient indicators between the two groups showed that the treatment group had a significantly higher mean age, a higher proportion of patients with abdominal infections, and a higher proportion of patients requiring hemofiltration therapy and norepinephrine to maintain blood pressure, C-reactive protein (CRP) levels increased and lymphocyte counts decreased, with higher Sequential Organ Failure assessment (SOFA) scores. The distribution of variables in the two groups is presented in Table 1.

Sepsis is a life-threatening clinical syndrome characterized by a dysregulated host response to infection, leading to profound and potentially fatal organ dysfunction (Kamath et al., 2023). Throughout this process, patients go through various stages, such as excessive inflammatory responses and immunosuppression. Despite active treatment, the mortality rate associated with sepsis is alarmingly high (Rudd et al., 2018). Finding new treatment methods is of significant value for sepsis. Omega-3 fatty acids are considered a potentially effective therapy. The expert consensus in USA recommends that for patients with sepsis who require parenteral nutrition, fish oil fat emulsion can be administered (Mundi et al., 2021). As the human body lacks the enzymes required for their synthesis, Omega-3 fatty acids are considered essential and must be acquired through dietary sources like fish oil (10g, Fresenius Kabi SSPC). The main physiological function of Omega-3 fatty acids is to regulate the body’s inflammatory response, alleviate immune suppression, thereby reducing tissue and organ damage, and improving prognosis (Calder, 2019; Zaloga, 2021; Notz et al., 2022a). The use of polyunsaturated FA in sepsis has a long history but it has been accompanied by significant controversy (Heller et al., 2011). Early randomized controlled trials suggested that fish oil did not confer any protective effects on organ failure in sepsis patients (Wohlmuth et al., 2010). However, other studies had indicated that fish oil may indeed have a beneficial effect on organ failure in sepsis patients (Hall et al., 2015). More and more positive evidences support the use of omega-3 FA in critically ill patients in the ICU (Singer and Calder, 2023). Several clinical studies have reported the efficacy of Omega-3 fatty acids in organ protection in sepsis. FA has been found to benefit various organ functions in sepsis patients. For instance, FA can inhibit excessive apoptosis of cardiomyocytes and improve myocardial damage in sepsis patients (Chen et al., 2023). Additionally, inhibiting the inflammatory response can have a protective effect on cardiomyocytes (Busch et al., 2021).FA can inhibit inflammation, improve lymphocyte immune function and reduce mortality in patients with sepsis induced intestinal failure (Chen et al., 2017).The study also found that indicators of liver function improved in patients with septic liver failure who received fish oil treatment (Badia-Tahull et al., 2015). Furthermore, liver disease induced by intestinal failure can benefit from Omega-3 FA, which act as anti-inflammatory agents and can reverse cholestasis (Bolia and Srivastava, 2019). For patients with acute lung injury, enteral nutrition formula rich inomega-3 PUFAs has positive effects on shortening mechanical ventilation time and reducing mortality (Singer et al., 2006). In sepsis patients with COVID-19, Omega-3 FA have demonstrated anti-inflammatory effects and can significantly reduce mortality (Erdem et al., 2023).Meta-analysis has shown that FA can reduce the 28-day mortality in severe patients (Notz et al., 2022a). However, the studies were mostly clinical trials rather than real-world studies.

To better assess the efficacy of omega-3 fatty acids in real-world medical settings, we conducted a retrospective review of data from 1,733 patients with sepsis, performing a real-world study. After excluding patients without pathogenic microbiome record and using propensity score matching, a total of 633 patients (422 controls and 211 treated) were included in the study. The mortality was 24.64% in the control group and 32.7% in the Omega-3 FA treatment group. The mortality of the treatment group was higher than that of the control group, which was different from previous research results (Chen et al., 2017),and there were significant differences in age, HF needed, NE needed, CRP, lymphocyte count, SOFA score and abdominal infection between the two groups. Although the crude mortality was higher in the ω-3 FA group, this finding reflects marked baseline imbalances rather than treatment harm. Patients receiving ω-3 FA supplementation were older and exhibited greater disease severity, including higher SOFA scores, more frequent hemofiltration and norepinephrine use, and higher inflammatory burden at ICU admission. These factors are independently associated with increased mortality in sepsis and likely biased the unadjusted comparison. After rigorous adjustment using multivariable models, propensity score matching, and IPTW to balance these prognostic indicators, ω-3 FAs consistently demonstrated a significant protective association with mortality, indicating that the crude unfavorable pattern primarily resulted from confounding. The study is a retrospective real-world study with data from hospital medical records. It is difficult to fully control and adjust confounding factors for patients entering the study based on their actual conditions. Previous studies have shown that the mortality of sepsis patients was significantly correlated with age, sofa score, infection site and other factors (Kim et al., 2024; Zhang et al., 2024).In the intensive care unit (ICU), critically ill patients necessitate increased equipment or medication support, indicating a more severe condition (Frank et al., 2021).One study identified age, Sequential Organ Failure Assessment (SOFA) score, use of vasopressors, and mechanical ventilation as independent risk factors for mortality (Liu et al., 2022).The above factors may affect the efficacy of Omega-3 fatty acids. So, we further performed univariate logistic regression analysis, and the statistical results showed that multiple factors, such as age, CRP, NE needed, etc, were significantly correlated with the mortality of patients with sepsis. After adjusting for age, HF needed, NE needed, CRP, lymphocyte count, SOFA score, and presence or absence of abdominal infection, multivariate logistic regression analysis showed that the protective effect of Omega-3 FA became apparent (HR 0.600, 95% CI 0.428, 0.828; p = 0.003). After adjustment, ω-3 FA supplementation was associated with a 35–45% relative reduction in mortality risk, which represents a clinically meaningful effect size in the context of sepsis, where even modest survival improvements are highly impactful. In addition, we found that age, CRP levels, and NE needed negatively affect the effectiveness of Omega-3 FA in treating sepsis. Age, CRP, and NE needed are key factors affecting the efficacy of Omega-3 FA.

According to the results of univariate logistic regression analysis and multivariate logistic regression analysis, we optimized the matching model in the follow-up study, and adopted IPTW to control confounding factors. The results showed that Omega-3 fatty acids had a good effect on reducing the mortality of sepsis, and the clinical consistency was good. After adjusting the survival curve with the aforementioned indicators, the survival analysis results show that Omega-3 fatty acids have a protective effect on the prognosis of sepsis. Previous clinical studies have mostly come from randomized controlled trials (RCTS), which tend to be conducted in specific populations, which may lead to limited application of the findings in practice. At the same time, there are many factors affecting the prognosis of sepsis, and it is difficult to explain the effect of single therapy only by direct comparison. Our study is the first real world study of Omega-3 fatty acids for sepsis; The significance of this study is the combination of Propensity Score Matching (PSM) and Inverse Probability of Treatment Weighting (IPTW). By controlling confounding variables and balancing the difference in baseline characteristics between different groups, the effect of randomized controlled trials was simulated to a certain extent, so as to estimate the treatment effect more accurately and obtain the average efficacy of treatment with Omega-3 fatty acids in the treatment group and the hypothetical control group. The study results suggest that the protective effect of Omega-3 fatty acids on mortality is consistent. It can better guide the clinical application of Omega-3 fatty acids. Therefore, based on the mechanism and clinical evidence, it was evident that Omega-3 FA had beneficial effects on inflammation reduction, organ protection, and cellular immunity in sepsis (Rosenthal et al., 2021). Although this study was conducted in a single-center retrospective real-world setting, this design also allowed evaluation of ω-3 FA therapy under routine clinical practice conditions, enhancing its clinical relevance. Because treatment was physician-directed rather than protocol-based, patients receiving ω-3 FA tended to be clinically more severe at baseline. While this inevitably introduced treatment-indication bias, it also provided an opportunity to assess potential benefit in high-risk patients. Advanced analytical approaches including multivariable adjustment, propensity score matching, and IPTW were applied to minimize confounding, and the consistency of results across multiple models strengthens confidence in the observed association, although causality cannot be definitively inferred. ω-3 FA administration occurred as part of parenteral nutrition, meaning treatment timing, duration, and cumulative dose varied naturally across patients. Rather than being a limitation alone, this reflects real-world heterogeneity and demonstrates applicability of findings to diverse ICU scenarios. Similarly, while inflammatory biomarkers such as cytokines were unavailable, routinely monitored indicators (CRP, PCT, WBC) still supported clinically meaningful biological plausibility. Immortal-time bias cannot be fully excluded because ω-3 FA typically began after stabilization; however, this reflects real-world constraints of nutrition initiation rather than methodological weakness. Importantly, these real-world observations generated a coherent signal suggesting that ω-3 FA use is associated with improved adjusted survival despite the treated group being initially sicker, highlighting meaningful clinical potential. Moving forward, multicenter prospective studies incorporating standardized treatment protocols, time-dependent exposure modeling, detailed nutritional assessment, and immune biomarker profiling will be valuable to validate these findings, better characterize biological mechanisms, and refine patient selection. Such studies will help translate this promising real-world evidence into optimized therapeutic strategies.

This retrospective analysis explored the link between ω-3 fatty acid supplementation and outcomes in sepsis patients. Omega-3 fatty acid supplementation was associated with reduced adjusted ICU mortality in sepsis; the study demonstrates that intravenous administration of ω-3 fatty acids confers a protective effect on mortality among ICU patients with sepsis after adjustment for confounding factors. These findings support the immunomodulatory and pro-resolving potential of ω-3 FA and justify their inclusion as an adjunctive therapeutic strategy in sepsis management. this conclusion was tempered by two key factors: the inherent limitations of the retrospective design, which preclude ruling out unmeasured confounding variables, and the higher crude mortality rate observed in the treatment group. Further confirmation requires well-powered prospective randomized controlled trials to clarify the efficacy, optimal dosage, and administration timing of ω-3 fatty acids for sepsis.