The association between 4-HPR-mediated LCN2 suppression and reduced intestinal cell senescence in ulcerative colitis

Ulcerative colitis is a type of inflammatory bowel disease that can significantly impact patients' life, leading to long-term complications. Cellular senescence plays a significant role in the occurrence and development of enteritis. The purpose of this study is to identify a specific drug and potential target that can inhibit intestinal cell senescence, thereby improving the clinical outcomes of enteritis. Bioinformatics analysis was used to identify the drug and target that associated with cellular senescence and ulcerative colitis. LPS-induced in vitro models and DSS-induced in vivo colitis models were used to confirm the association between colitis and aging, as well as the ability of the drug to alleviate colitis symptoms. Bioinformatics analysis suggested that Fenretinide (4-HPR) may influence the progression of ulcerative colitis by targeting LCN2 to modulate cellular senescence. Western blot analysis revealed high expression of LCN2 in patients with ulcerative colitis (p- value < 0.05). In the in vivo experiments utilizing a DSS-induced colitis model, 4-HPR was shown to be both safe and effective in inhibiting colitis progression. Western blot analysis indicated the downregulation of the senescence markers P16 and P21 following 4-HPR treatment (adjusted p-value < 0.0001). Moreover, β-galactosidase staining of intestinal tissues revealed a reduction in the accumulation of senescent cells in the 4-HPR-treated group compared to the DSS group (adjusted p-value < 0.0001). The potential mechanism might be related to the regulation of the Treg/Th17 balance. 4-HPR reduced the intestinal cell senescence by inhibiting the expression of LCN2 that alleviated the symptoms of ulcerative colitis.