Sepsis represents a significant public health challenge, characterized by high morbidity and mortality rates of up to approximately 30%, and poses a serious threat to patients’ lives in both general hospital wards and intensive care units (ICU) (Wang et al., 2021). Sepsis is defined as life-threatening organ dysfunction resulting from an uncontrolled host immune response to infection (Singer et al., 2016). In essence, this dysregulated immune response not only fails to protect the body from infection, but also exacerbates the systemic inflammatory response, leading to damage across multiple organs. Among the various organs affected by multi-organ dysfunction in sepsis, the lungs are often the earliest and most susceptible to invasion (Sadowitz et al., 2011; Park et al., 2019). Research indicates that 25%–50% of sepsis patients will induce acute lung injury (ALI), with mortality rates in these patients potentially reaching as high as 40% (Sevransky et al., 2004; Rubenfeld et al., 2005). This highlights that ALI is a particularly dangerous complication during the course of sepsis and has a substantial impact on patient prognosis. Clinically, patients with ALI typically present with systemic inflammatory response syndrome, characterized by refractory hypoxemia and severe respiratory distress (Martin and Silverman, 1992; Jin et al., 2020). These symptoms not only significantly impair the patient’s quality of life but also necessitate advanced medical support, such as mechanical ventilation and intensive care interventions to sustain life. For these patients, timely risk stratification can reduce mortality.

In the field of sepsis research, various biomarkers have been extensively studied and established as important indicators for detection and prognosis. These biomarkers include interleukin 6 (IL-6), C-reactive protein (CRP), interleukin 8 (IL-8), tumor necrosis factor-α (TNF-α), and interleukin 1β (IL-1β), along with their combinations (Carcò et al., 2022; Li, 2024; Zeng et al., 2022). Our study specifically focuses on interleukin 34 (IL-34) due to its novel role in regulating immune responses, particularly in the context of sepsis. IL-34, a cytokine first described in 2008 (H. Lin et al., 2008), is secreted by the monocyte-macrophage system, epithelial cells, and fibroblasts, and is continuously expressed in various tissues and organs, including the human heart, lungs, and spleen (Muñoz-Garcia et al., 2021). Numerous previous studies have demonstrated that IL-34 plays a significant role in various cancers, autoimmune diseases, and inflammatory conditions (Preisser et al., 2014; Zhou R. et al., 2016; Zhou S. et al., 2016; Zwicker et al., 2015). Additionally, research has indicated that IL-34 is associated with respiratory diseases such as pneumonia and interstitial lung disease (Kuzumi et al., 2018; Tang et al., 2024). Recent studies have underscored the relationship between IL-34 and sepsis, illustrating its potential role in mediating immune responses. For instance, Jacobs and Wiersinga (2018) discussed IL-34 as an emerging factor in sepsis, proposing that it may influence pathogenic processes related to systemic inflammation and organ dysfunction. Furthermore, Lin et al. (2018) provided compelling evidence that IL-34 contributes to improved survival and bacterial clearance in polymicrobial sepsis, emphasizing its importance in the host response to infection. It is important to clarify that this study does not seek to diminish the significance of established biomarkers; rather, it aims to explore the novel and understudied role of IL-34 in sepsis.

Currently, there is limited direct data regarding the relationship between IL-34 and sepsis patients, and no reports have been published on the role of IL-34 in patients with sepsis-induced ALI. Therefore, this study aimed to investigate the potential of IL-34 as a biomarker for both sepsis and sepsis-induced ALI. We hypothesized that elevated levels of IL-34 would correlate with the severity of sepsis and sepsis-induced ALI, thereby serving as a reliable prognostic marker. The primary objective of this study was to determine whether IL-34 can predict outcomes in ICU patients suffering from sepsis and sepsis-induced ALI.

The current study identifies IL-34 as an independent prognostic factor for survival in sepsis patients. A cutoff value of 130.05 pg/mL was established for stratifying patients at high risk of mortality. Additionally, IL-34 demonstrated a positive correlation with inflammatory biomarkers and disease severity. The prognostic value of IL-34 for survival was better than that of other inflammatory biomarkers including IL-6, CRP, and PCT. Our findings also suggest that IL-34 may serve as a valuable risk stratifier for sepsis-induced ALI. Additionally, we present the first preliminary investigation into the prognostic significance of IL-34 within this patient population.

Sepsis is widely recognized as a disease characterized by a systemic inflammatory response. Recent studies have increasingly highlighted IL-34 as a significant regulator of inflammatory responses and related diseases. Elevated levels of IL-34 have been associated with the severity of rheumatoid arthritis and poor prognosis (Zhou et al., 2016). Additionally, serum IL-34 levels in patients with systemic sclerosis have been reported to increase with the severity of interstitial lung disease (Kuzumi et al., 2018). Furthermore, IL-34 has been demonstrated to play a crucial role in hepatitis C-related liver fibrosis (Preisser et al., 2014). This study found that IL-34 is highly expressed in sepsis group and non-survival group, with expression levels correlating with disease severity. These findings align with previous research on IL-34 in inflammatory diseases. Additionally, Jacobs and Wiersinga (2018) identified IL-34 as an emerging factor in sepsis, suggesting its potential influence on pathogenic processes related to systemic inflammation and organ dysfunction. Research by Lin et al. (2018) also indicates that IL-34 is highly expressed in sepsis patients and may enhance survival rates and bacterial clearance in cases of polymicrobial sepsis, further underscoring the relationship between IL-34 and sepsis. However, a conflicting result observed by Lin et al. was that IL-34 levels did not correlate with APACHE II score or SOFA score in sepsis patients. This may be attributed to subtle differences in disease severity, ethnic background, sample size, and the criteria used for selecting sepsis patients. Another notable difference is that our study demonstrates a positive correlation between serum IL-34 levels and IL-6, PCT, and lactate levels during the onset of sepsis patients, which is also associated with prognosis. In contrast, Lin et al. did not investigate these relationships.

In the field of sepsis research, numerous biomarkers have been recognized, such as TNF-α, IL-8, IL-6, and CRP (Carcò et al., 2022; Li, 2024; Zeng et al., 2022). TNF-α, a classic pro-inflammatory factor, is rapidly released during the early stages of the inflammatory response and is significantly correlated with mortality in sepsis (Gharamti et al., 2022). IL-8, a potent chemokine, is closely associated with the risk of early mortality in sepsis and has a strong relationship with the SOFA score and multi-organ dysfunction (Livaditi et al., 2006). Our findings regarding IL-34 align with these observations: IL-34 is associated with sepsis severity and poor prognosis. Furthermore, we developed a univariate Cox regression model using age, gender, IL-34, IL-6, PCT, CRP, LAC, GCS score, SOFA score, and APACHE II score as independent variables. Our analysis indicated that the prognostic value of IL-34 surpasses that of IL-6 and CRP. It is important to clarify that our study specifically focused on IL-34 and did not aim to undermine the significance of established biomarkers. Rather, it sought to investigate the novel and underexplored role of IL-34 in sepsis. For future research, we recommend further examination of the use of IL-34 in conjunction with established biomarkers to enhance early diagnosis and risk stratification of sepsis.

Current research indicates that IL-34 is associated with the prognosis of various diseases. Previous studies have demonstrated that elevated levels of IL-34 correlate with poor outcomes in patients with heart failure, particularly those with chronic renal failure or insufficiency (Tao et al., 2017). Additionally, increased serum IL-34 levels upon admission are linked to a higher risk of acute ischemic stroke and are associated with diminished functional outcomes (Huang et al., 2021). Similarly, we explored the relationship between IL-34 and prognosis in sepsis patients. In our study, the ROC curve indicated that serum IL-34 exhibited enhanced clinical screening sensitivity and predictive value when compared to the SOFA score alone. Additionally, the results from the Kaplan-Meier survival analysis and the multifactorial Cox regression model indicated that IL-34 functions as an independent risk factor for 28-day mortality in sepsis patients, establishing a critical threshold of 130.05 pg/mL for identifying high-risk individuals. Therefore, these results suggest that serum IL-34 is associated with poor prognosis in sepsis patients.

ALI is a particularly dangerous complication of sepsis and significantly impacts patient prognosis. Notably, our study revealed that the proportion of ALI patients in the non-survival group was markedly higher than that in the survival group. Numerous previous studies have established a correlation between IL-34 and various respiratory diseases. For instance, Tang et al. (2024) reported a relationship between serum IL-34 levels and the severity in patients with community-acquired pneumonia. Additionally, another study indicated that IL-34 levels are elevated in patients with systemic sclerosis and are strongly linked to the incidence and severity of interstitial lung disease (Kuzumi et al., 2018). Furthermore, one investigation demonstrated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection significantly increases human IL-34 levels (Kaufmann et al., 2023). Consequently, we further categorized sepsis patients to explore the relationship between serum IL-34 and prognostic outcomes in those with ALI. In our study, we observed that the serum IL-34 level in the ALI group was significantly higher than that in the non-ALI group. Moreover, serum IL-34 levels were significantly elevated in patients with severe ALI compared to those with mild to moderate ALI. These findings suggest a potential association between IL-34 levels and the severity of ALI, which may provide valuable insights into the risk stratification of sepsis-induced ALI. Subsequently, we conducted a preliminary exploration of the prognostic value of IL-34 in this patient population using Kaplan-Meier curves and univariate Cox proportional hazards models. Although the results suggested that elevated IL-34 levels may be associated with poorer patient prognosis, none of the differences reached statistical significance. However, this does not imply that IL-34 lacks clinical relevance in these patients; rather, its effects may be obscured by various confounding factors. Therefore, we accounted for confounding variables such as age, sex, and comorbidities and applied multiple Cox regression analysis. The results indicated that, after adjusting for these confounding factors, the hazard ratio for IL-34 remained close to 1, underscoring the necessity for further studies on its prognostic value in sepsis-induced ALI. We recommend that future research consider additional confounding factors, such as pathogen type, nutritional status, and therapeutic interventions, and conduct larger prospective studies to further investigate the potential role of IL-34 in this pathological context.

This study has several limitations. First, the research was conducted at a single institution with a limited sample size, which may affect the generalizability and external applicability of the findings. Consequently, larger multicenter studies are warranted to validate these results and assess their clinical relevance. Second, the established IL-34 thresholds have not been externally validated or tested in independent cohorts or across multiple centers; thus, further studies are necessary to confirm their accuracy and applicability in diverse patient populations. Additionally, due to the limited availability of patient sera, we were unable to detect other biomarkers associated with sepsis, such as TNF-α, IL-1β, and IL-8. Furthermore, we did not evaluate the dynamic changes of IL-34 in all sepsis patients. Owing to various practical challenges, we only collected 22 consecutive serum samples from the original 115 patients. Although our results indicate that IL-34 levels changed during the first 5 days of hospitalization, we acknowledge that the small sample size may limit the statistical power and generalizability of our findings. It is essential to regard these results as an initial step in understanding IL-34 dynamics rather than a definitive conclusion. We sincerely hope that future studies with larger sample sizes will further validate and extend our observations.

In conclusion, IL-34 has been identified as an independent risk factor for predicting 28-day mortality in sepsis patients. It may serve as a potential biomarker for risk stratification in sepsis-induced ALI; however, the prognostic value of IL-34 in this particular patient population needs to be fully elucidated with a larger sample size and by considering more confounding factors in future studies.