Ulcerative colitis (UC), a predominant form of inflammatory bowel disease (IBD), is a chronic and relapsing intestinal inflammatory disorder [1]. Despite extensive research, the precise etiology of UC remains incompletely understood, with contributing factors including genetic susceptibility, disruption of the epithelial barrier, immune dysregulation, and environmental influences [2]. In recent decades, the incidence of UC has risen markedly [3]. Current therapeutic strategies, including mesalazine, glucocorticoids, immunosuppressants, and biological agents, offer relief; however, disease recurrence and adverse side effects persist in certain patient populations [4]. Consequently, the identification of novel therapeutic targets is crucial for advancing treatment options.

Estrogen receptors (α, β, and G-protein coupled receptor), play a critical role in regulating a variety of physiological processes [5]. Estrogen receptor β (ERβ), the predominant subtype expressed in intestinal epithelial cells (IECs) in both males and females, not only mediates estrogen signaling but also functions independently as a transcription factor [6]. Beyond its role in estrogen-driven processes, ERβ can exert cellular effects as a standalone protein or in conjunction with other regulatory proteins, and is essential for maintaining the structural and functional integrity of the intestinal epithelium [7]. Emerging evidence suggests that ERβ exerts significant anti-inflammatory and antitumor effects in the colon, with mechanisms potentially involving the modulation of the microbiota, immune responses, and the preservation of epithelial barrier function[[8], [9], [10]]. However, the exact molecular pathways through which ERβ regulates IECs remain incompletely understood.

ERB041 is a selective, nonsteroidal ERβ agonist that has been shown to specifically activate ERβ signaling without affecting ERα [11]. By selectively targeting ERβ, ERB041 has emerged as a promising therapeutic agent for modulating ERβ-mediated pathways in a variety of physiological contexts, including inflammatory and oncological disorders [8]. Recent studies have demonstrated that ERβ agonist can ameliorate inflammation and promote epithelial barrier function, making it a potential candidate for the treatment of inflammatory diseases such as UC [12]. Despite these promising findings, the full range of molecular mechanisms underlying the effects of ERB041 in the intestinal epithelium remains to be fully elucidated.

Macroautophagy, commonly referred to as autophagy, is a highly conserved metabolic process initially described by Yoshinori Ohsumi [13]. Regulated by an intricate network of autophagy-related genes (ATGs), autophagy involves several key stages: the formation of phagosomes, the generation of autophagosomes, and their subsequent fusion with lysosomes to form autolysosomes [14]. This process facilitates the degradation of intracellular components, thereby maintaining cellular homeostasis [15]. Autophagy plays a pivotal role in the development and progression of various diseases, including IBD [16]. In the context of intestinal health, autophagy helps sustain intestinal homeostasis and exerts anti-inflammatory effects by preserving the function of IECs, modulating the intestinal immune response, regulating the microbiota, and maintaining overall intestinal physiology [15].

In patients with UC, autophagy is significantly impaired in the inflammatory regions of the colon compared to normal colonic mucosa [17]. Similarly, in experimental models of colitis, such as dextran sulfate sodium (DSS)-induced colitis in mice, autophagy is downregulated [18]. Notably, interventions with autophagy agonists have shown promise in ameliorating UC symptoms and alleviating intestinal inflammation [18].

At the molecular level, autophagy is regulated by a complex network of signaling pathways, with key regulators including mTOR, AMPK, and hypoxia-inducible factor 1α (HIF-1α) [19]. As a transcription factor, HIF-1α can regulate the cellular adaptation to low oxygen levels and support the development and function of the gut barrier [20]. HIF-1α enhances the cellular response to hypoxia, facilitating autophagic flux as a means of cellular survival. This mechanism is particularly relevant in tissues such as the gut, where oxygen availability fluctuates and the demand for autophagic activity is high [21]. Additionally, ERβ has been shown to modulate autophagy in certain neoplastic conditions, such as breast cancer and osteosarcoma, highlighting its potential role in regulating autophagic processes in the colon as well [22,23].

Building on these observations, we hypothesized that ERβ may mitigate intestinal inflammation through the regulation of HIF-1α and autophagy. To test this hypothesis, we examined the expression of ERβ in both inflammatory and non-inflammatory colon tissues from patients with UC. We further investigated the underlying mechanisms using a murine model of DSS-induced colitis and an in vitro inflammation model with lipopolysaccharide (LPS)-treated HT-29 cells. Our results provide compelling evidence for ERβ as a potential therapeutic target in UC, acting through the activation of autophagy, and highlight a novel mechanistic pathway that could be exploited for therapeutic intervention in UC.