The International Diabetes Federation reports that the global prevalence of diabetes among individuals aged 20–79 reached 536 million in 2021, with projections indicating an increase to 783 million by 2045 [1]. Type 2 diabetes mellitus (T2DM) accounts for approximately 90% of all diabetic cases worldwide, making it the predominant subtype [2]. T2DM is a progressive metabolic disorder characterized by pancreatic β-cell dysfunction and peripheral insulin resistance. Patients with T2DM often experience chronic low-grade inflammation, which is triggered by insulin resistance and serves as a critical driver of disease progression [3]. This chronic inflammation can further promote pyroptosis, a form of programmed cell death marked by cell swelling, membrane rupture, and the release of inflammatory cytokines [4]. Recent evidence suggests that the NLRP3-mediated classical pyroptosis pathway plays a significant role in T2DM development [5,6]. However, the involvement of other pyroptosis factors in T2DM remains inadequately understood and warrants further investigation.

Interferon regulatory factor 2 (IRF2), a member of the interferon regulatory factor family of transcription factors, plays crucial roles in immune responses and cell differentiation by transcriptionally regulating key target genes, such as centromere protein N (CENP-N) and gasdermin D (GSDMD) [[7], [8], [9]]. GSDMD, a central protein in the gasdermin family, acts as a substrate for inflammatory Caspases (Caspase-1/−4/−5/−11), whose cleavage generates the active N-terminal fragment of GSDMD (GSDMD-N), leading to pyroptotic cell death [10]. A genome-wide screening study has shown that in a pyroptosis model of human monocyte-derived macrophages induced by lipopolysaccharide (LPS), only three genes—Caspase-4, GSDMD, and IRF2—are significantly associated with pyroptosis, with IRF2 playing a critical role by directly regulating Caspase-4 levels [11]. Suppressing IRF2 expression has been shown to reduce cellular pyroptosis in diabetic nephropathy, thereby mitigating renal injury [12]. However, the potential role of IRF2 in regulating pancreatic islet cell damage through the Caspase-4/GSDMD pyroptosis pathway remains unexplored.

The maintenance of normal bodily functions relies on a delicate balance of dietary trace elements, as both deficiency and excess can precipitate various health issues [13,14]. Notably, the pathogenesis of T2DM is influenced not only by inflammatory mediators but also by this critical balance of trace element intake. Selenium (Se), an essential trace element, plays a pivotal role in regulating lipid and glucose metabolism [15]. Despite its importance, the narrow safety margin of Se intake means that a universally accepted threshold for safe consumption has not been established [16]. Historically, Se was thought to exert therapeutic effects in T2DM due to its antioxidant and anti-inflammatory properties. However, observational studies have found that higher plasma Se levels are associated with a higher incidence of T2DM [17]. Genetic interactions between Se and polymorphisms in redox/insulin-signaling genes provide a biological basis for the observed association between Se concentrations and diabetes prevalence [18,19]. Additionally, the mechanisms by which Se regulates the classical NLRP3/Caspase-1/GSDMD pyroptosis pathway via reactive oxygen species (ROS) have been well-characterized [20]. However, it remains unclear whether Se exposure directly triggers pyroptosis through the non-canonical IRF2/Caspase-4/GSDMD pathway, thereby impairing insulin secretion.

In summary, we hypothesize that Se exposure may initiate inflammatory responses by modulating the IRF2/Caspase-4/GSDMD non-canonical pyroptosis pathway, contributing to the development of T2DM. To investigate this, we will establish both in vivo and in vitro models of Se exposure. Se levels in biological samples will be quantified using inductively coupled plasma mass spectrometry (ICP-MS). To verify whether Se induces pyroptosis, we will employ disulfiram (DSF), a specific GSDMD inhibitor, to block the process [21]. Furthermore, to explore the role of IRF2, we will generate IRF2-knockdown cell lines using lentiviral vectors and examine the specific contribution of IRF2 to pyroptosis under Se exposure.