Inflammatory bowel disease (IBD) represents a chronic, nonspecific inflammatory condition of the gastrointestinal tract with obscure etiology and a multifactorial pathogenesis. Clinically, disorders such as ulcerative colitis (UC) and Crohn's disease (CD) are encompassed within it [1,2]. Since the mid-20th century, there has been a substantial increase in IBD incidence and prevalence, with the disease becoming one of the most common gastrointestinal disorders in the 21st century [3,4] The primary clinical manifestations of IBD include abdominal pain, diarrhea, bloody stools, and weight loss. Neutrophils and macrophages infiltrate the affected areas in large numbers, releasing pro-inflammatory mediators such as cytokines, proteases, and reactive oxygen species, which lead to inflammation and ulceration [1,2].

Cyclic GMP-AMP synthase (cGAS) recognizes microbial or self-derived double-stranded DNA (dsDNA), including that from bacterial, viral, or endogenous origins such as the nucleus or mitochondria [5]. Upon dsDNA recognition, downstream signaling pathways are activated, initiating inflammatory immune responses [6]. Upon binding to dsDNA, the catalytic center of cGAS undergoes a conformational change [7], and it uses ATP and GTP as substrates to produce the second messenger 2′,3′-cyclic GMP-AMP (cGAMP) [8,9]. As both a second messenger and an endogenous ligand, cGAMP binds to and activates the endoplasmic reticulum-localized stimulator of interferon genes (STING) [[10], [11], [12]]. Once activated, STING (encoded by the TMEM173 gene) translocates to the Golgi apparatus and recruits TANK-binding kinase 1 (TBK1) and IκB kinase, among other signaling molecules. These activated kinases phosphorylate interferon regulatory factor 3 (IRF3) [13] and nuclear factor-κB (NF-κB) [14]. Phosphorylated IRF3 undergoes nuclear translocation, where it induces the transcription of type I interferon (IFN-I) genes. In parallel, activated NF-κB migrates to the nucleus and upregulates pro-inflammatory cytokines, including interleukin-6 (IL-6), tumor necrosis factor (TNF), and IFN-I genes [15].

The cGAS-STING pathway, a key cytosolic DNA-sensing mechanism, is significantly upregulated in IBD and plays a complex dual role in intestinal homeostasis and inflammation [16]. It is activated by microbial or self-derived double-stranded DNA from multiple sources, including mucosal injury, mitochondrial release, and neutrophil extracellular traps (NETs) [17]. This triggers the production of the second messenger cGAMP, STING activation, and subsequent TBK1-IRF3 signaling, leading to robust type I interferon and pro-inflammatory cytokine production [[13], [14], [15],18,19]. Such responses engage innate and adaptive immune cells-such as dendritic cells via the STING-IL-12 axis and M1 macrophages-promoting barrier dysfunction, T cell polarization, and overall immune imbalance [20,21]. Although under physiological conditions the pathway helps maintain intestinal homeostasis by regulating protective immunity [22], its persistent activation drives chronic inflammation and pathology in IBD, highlighting its potential as a therapeutic target for intervention.

Acetylation, a key epigenetic modification regulated by histone deacetylases (HDACs), influences gene expression and immune responses [23,24]. HDAC inhibitors have been shown to modulate cGAS activity and expression [25,26]. In this study, we screened a library of epigenetic drugs and identified panobinostat, an HDAC inhibitor, as a potent suppressor of the cGAS-STING pathway. We further demonstrated its efficacy in ameliorating DSS-induced colitis in mice, suggesting its potential as a therapeutic agent for IBD.