Sepsis-induced pulmonary injury (SPI), also referred to as sepsis-associated acute lung injury (ALI), is a severe complication of sepsis characterized by diffuse alveolar damage, increased vascular permeability, and inflammatory cell infiltration, resulting in respiratory failure(Wang and Wang, 2023). SPI represents a major cause of morbidity and mortality in critically ill patients, particularly in intensive care units (ICUs). Established risk factors include severe infections, prolonged hospitalization, and pre-existing conditions such as chronic lung diseases. Current treatments focus on supportive care, including mechanical ventilation, antibiotics, and anti-inflammatory therapies(Sevransky et al., 2004). However, the absence of targeted therapies combined with the complexity of its pathogenesis presents significant challenges. Inflammation drives SPI progression, as excessive immune activation and pro-inflammatory cytokine release (e.g., interleukin [IL]-6, tumor necrosis factor [TNF]-α, and IL-1β) exacerbate tissue damage and impair lung function(Kumar, 2020). Elucidating the molecular mechanisms governing SPI-related inflammation is critical for developing effective therapies.

5-methylcytosine (m⁵C) modification is a key epigenetic marker that regulates gene expression(Gao and Fang, 2021). This process involves methyl group addition to the cytosine ring's fifth carbon, predominantly in CpG dinucleotides. These modifications are catalyzed by RNA methyltransferases, including the NOP2/Sun (NSUN) family(Li et al., 2022). NSUN3, a well-studied enzyme, mediates m⁵C modification in mitochondrial tRNA, thereby modulating mitochondrial function and cellular energy metabolism(Delaunay et al., 2022). Emerging evidence implicates NSUN3 in diverse diseases, such as cancer and metabolic disorders. For example, NSUN3 knockdown suppresses colorectal cancer cell proliferation and migration via antiproliferative and pro-apoptotic effects(Tang et al., 2024). Additionally, NSUN3-mediated mitochondrial tRNA 5-formylcytidine modification is essential for embryonic development and respiratory complex assembly(Murakami et al., 2023). Nevertheless, its role in inflammatory diseases, specifically SPI, remains elusive.

Transforming growth factor β-activated kinase 1 (TAK1), a serine/threonine kinase, orchestrates inflammation and immune responses(Ma et al., 2023). As a core component of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) pathways, TAK1 activates downstream signaling in response to pro-inflammatory cytokines and microbial pathogens(Li et al., 2024). TAK1 dysregulation contributes to inflammatory diseases by promoting inflammatory mediator release and tissue damage, as observed in diabetic kidney disease and lipopolysaccharide-induced lung injury(Chen et al., 2022; Zhao et al., 2024). Despite its well-documented role in inflammation, the mechanisms regulating TAK1 expression and activity, particularly post-transcriptional regulation, are not fully defined.

This study sought to identify differentially expressed genes (DEGs) in SPI and investigate their inflammatory roles, potentially providing a scientific basis for targeted therapies to address unmet clinical needs in SPI management.