Sepsis, characterized by organ failure resulting from an aberrant host response to infection, is commonly observed in patients suffering from severe trauma or infectious diseases(Boehm and Menke, 2021; Cecconi et al., 2018). The morbidity and death rates of sepsis have diminished due to advancements in diagnostic and therapeutic tactics. However, its pathogenesis remains unclear(Cron et al., 2023; Vincent et al., 2019). Given the life-threatening nature of sepsis, it is essential to investigate the molecular mechanisms of sepsis to formulate effective strategies for its prevention and management.

N6-methyladenosine (m6A), an important post-transcriptional modification widely found in eukaryotic mRNA, is characterized by methylation at the N6 position of adenosine(He et al., 2019). Numerous studies have shown that m6A modification regulates many biological processes and contributes to the pathogenesis of various diseases(Deng et al., 2023; Ding et al., 2024; Jiang et al., 2021). m6A modification is invertible and dynamic and is regulated by m6A methyltransferases and demethyltransferases(Jiang et al., 2021; Zaccara et al., 2019). When RNA undergoes m6A modification, it recruits m6A reading proteins (YTH domain-containing proteins, [YTHDC1-2]) to recognize the m6A modification, therefore modulating RNA expression(Widagdo et al., 2022; Zeng et al., 2023b). Accumulating evidence has shown that METTL3 is involved in various inflammatory diseases, including sepsis, atherosclerosis, and diabetes(Dong et al., 2024; Li et al., 2021; Shi et al., 2025). Nevertheless, the function of METTL3 in the regulation of inflammation remains uncertain. High-mobility group box 1 (HMGB1) is a prevalent nuclear protein that stabilizes nucleosomes and is involved in regulating DNA transcription and repair. HMGB1 is passively released from damaged cells or directly secreted into the extracellular space by activated immune cells. It functions as a pro-inflammatory cytokine and participates in inflammation-driven diseases, such as sepsis(Kleinschmidt et al., 1990; Schiraldi et al., 2012; Tang et al., 2023). Clinical evidence shows that the concentration of HMGB1 in plasma is remarkably higher in patients with sepsis and is correlated with the severity and mortality rates of the disease(Karakike et al., 2019). Therefore, inhibiting HMGB1 release represents a promising strategy for suppressing inflammation in patients with sepsis. Interestingly, sirtuin 1 (SIRT1), a NAD + -dependent deacetylase, has been shown can effectively reduce HMGB1 acetylation, thereby diminishing its extracellular release in lipopolysaccharide (LPS)-induced macrophage cells(Chen et al., 2018; Rabadi et al., 2015; Wei et al., 2019). However, whether METTL3 influences the release of HMGB1 and whether this effect is related to SIRT1 in sepsis remains unclear.

In this investigation, we discovered that METTL3-mediated m6A modification attenuated inflammatory responses by increasing SIRT1 expression in a YTHDC1-dependent manner, suppressing the release of HMGB1 in vitro and in vivo. These findings provide novel insights into the role of m6A modification in regulating inflammation during sepsis, suggesting that targeting METTL3 is a promising treatment strategy for sepsis.