Sepsis is a life-threatening condition characterized by an excessive immune response to infection that leads to multiple organ dysfunction [1,2]. Globally, sepsis remains one of the top ten causes of death, with incidence increasing by about 1.5 % each year [3]. Recent epidemiological studies estimate that sepsis accounts for 19.7 % of global deaths, with 11 million deaths out of 48.9 million new cases annually [4]. Among these cases, pediatric sepsis is particularly concerning, affecting approximately 20 million children annually, with children under five years old being the most vulnerable [[4], [5], [6]].

Among the multiple organ dysfunctions of sepsis, acute lung injury (ALI) is one of the most common and severe complications [7,8]. Sepsis-induced ALI significantly increases morbidity and mortality and is highly likely to develop into acute respiratory distress syndrome (ARDS), which has a mortality rate of 30 %–40 % [9].

The pathophysiology of sepsis-induced ALI involves a complex interplay of inflammatory cascades, oxidative stress, and immune dysfunction [10,11]. The initial hyperinflammatory response leads to excessive production of reactive oxygen species (ROS) and cytokines, causing tissue damage. Subsequently, immunosuppression results in impaired host defenses and increased susceptibility to secondary infections [12,13]. Recent studies have identified ferroptosis, a unique form of iron-dependent cell death characterized by lipid peroxidation, is a critical factor in sepsis-induced ALI [14]. Excessive ROS production during sepsis damages endothelial cells and aggravate lung injury [15,16]. Ferroptosis not only directly impairs cell survival, but also alters the immune microenvironment, promotes systemic inflammatory response, and accelerates disease progression. However, the exact molecular mechanisms of immune dysfunction in sepsis remain unclear and require further research to develop potential therapeutic targets.

Mitogen-activated protein kinase 14 (MAPK14), also known as p38α, is a member of the mitogen-activated protein kinase family. It is an important regulator of inflammatory responses and cellular stress [17]. Previous research suggests that MAPK14 plays a role in immune regulation and lipopolysaccharide (LPS)-induced sepsis [18,19]. However, its involvement in ferroptosis and immune cell infiltration within the context of sepsis-induced ALI has not been fully elucidated.

We investigated the role of MAPK14 in the pathogenesis of sepsis-induced ALI, with a particular focus on its regulation of ferroptosis and immune cell infiltration. Using bioinformatics analysis, clinical sample evaluation, in vitro cellular assays, and an in vivo cecal ligation and puncture (CLP) mouse model, we examined how MAPK14 influenced oxidative stress, ferroptotic pathways, and immune modulation. We hypothesized that MAPK14 promoted inflammatory responses and ferroptosis through activation of the TTP53/SLC7A11/GPX4 pathway, while exacerbating immune suppression by enhancing neutrophil infiltration. By exploring the mechanistic role of MAPK14 in sepsis-induced ALI in pediatric patients, this study may provide novel insights into its potential as a therapeutic target for sepsis and its associated complications.