Sepsis, a complex and rapidly developing clinical condition, is characterized by systemic inflammatory response syndrome caused by infection and frequently leads to multiple organ failure (Salomão et al., 2019). Although the continuous updating of anti-infective treatment and support methods in recent years has improved the survival rate of patients with sepsis, the mortality rate remains high (Srzić et al., 2022). Acute respiratory distress syndrome (ARDS), a common and severe complication of sepsis, is a leading cause of mortality in septic patients due to its early onset, rapid progression, and critical condition (Meyer et al., 2021). It has been reported that the pathogenesis of ARDS mainly focuses on inflammatory storm, alveolar epithelial cell apoptosis, excessive oxidative stress and coagulation dysfunction (Bos and Ware, 2022), but the exact molecular mechanism is still unclear. Therefore, conducting an in-depth investigation into the pathogenesis and mechanisms of ARDS holds critical clinical significance in its prevention and treatment.

Ferroptosis is a new form of programmed cell death (Li et al., 2020). Its mechanism is mainly related to intracellular iron accumulation, glutathione peroxidase 4 (GPX4) inactivation and reactive oxygen species (ROS) metabolism, which further promotes production of inflammatory factors (such as TNF-α, IL-1β and IL-6) and toxic lipid peroxidation products such as malondialdehyde (MDA), resulting in more serious damage (Jiang et al., 2021). Studies have shown that inhibition of ferroptosis can improve sepsis-induced lung injury (Wang et al., 2022a; Zhang et al., 2022), indicating that targeting ferroptosis may be a potential strategy for treating sepsis-induced ARDS. Sestrin 2 (SESN2), a protein encoded by the human SESN2 gene, belongs to the sestrins (SESNs) protein family and has the effects of anti-oxidation, improving autophagy level, and protecting cells against various stress responses (Luo et al., 2020; Li et al., 2021; Liu et al., 2023). It has been reported that SESN2 protects against traumatic brain injury through activating nuclear factor-erythroid 2-related factor 2 (Nrf2) (Liu et al., 2021a), which is an important factor in inhibiting ferroptosis (Abdalkader et al., 2018; Dodson et al., 2019). Importantly, SESN2 exerts a pivotal role in alleviating sepsis and its induced organ damage (Kim et al., 2016; Wang et al., 2019). It is worth noting that SESN2 exhibits a protective effect against LPS-induced acute lung injury by inducing mitophagy in macrophages (Wu et al., 2021). However, the precise biological role and mechanism of action of SESN2 in sepsis-induced ARDS remain poorly elucidated in literature.

Zinc finger protein ZNF384 (ZNF384) gene encodes a C2H2 type zinc finger protein. As a transcription factor, ZNF384 plays a key role in many cellular processes and diseases (Wan et al., 2019; Zhu et al., 2023). ZNF384 is a transcriptional activator of aquaporin 5 (AQP5) (Rump et al., 2016). APQ5 has been proved to be significantly down-regulated in septic lung injury rats, and its expression level is associated with the degree of pulmonary edema and inflammation (Sun et al., 2015; Jin et al., 2013; Xu et al., 2016). Moreover, APQ5 has also been reported to associate with oxidative stress (Wang et al., 2023). From these observations, the potential correlation between ZNF384 and sepsis-induced ARDS can be inferred. Furthermore, ZNF384 has also been shown to be associated with DNA double-strand break repair process (Singh et al., 2021). Interestingly, DNA double-strand breaks are related to lung epithelial cell toxicity, oxidative stress, and apoptosis (Kamp et al., 1995; Ollikainen et al., 1998; Jung et al., 2000; Upadhyay and Kamp, 2003). Thus, ZNF384 may be a crucial regulatory factor in the process of sepsis-induced lung injury. However, the research about ZNF384 in sepsis-induced ARDS is lacking.

Here, we investigated the role and mechanism of ZNF384 in ARDS. We proposed that ZNF384 promoted autophagy activation by transcriptional activation of SESN2, thereby inhibiting LPS-induced ferroptosis and inflammation, suggesting that targeting ZNF384 may be an effective strategy for ARDS treatment.