Identification of TIMP1 as a Key Regulator of Ferroptosis in Ulcerative Colitis Through Bioinformatics and Functional Experiments
Abstract
Background: Ferroptosis is an iron-dependent form of regulated cell death, whereas the precise mechanism of ferroptosis in the pathogenesis of ulcerative colitis (UC) remains to be elucidated. The tissue inhibitor Metalloproteinase 1 (TIMP1) is involved in ferroptosis of UC, whereas its regulatory function remains unclear. This study is aimed at exploring the potential effect on ferroptosis in UC.
Methods: Gene expression profiling data of colonic biopsies from UC patients and healthy controls were acquired from the GSE87466 dataset. The expression of TIMP1, GPX4, and SLC7A11 was determined using western blot. The mRNA levels of TIMP1, PGRMC1, IL-1β, and IL-6 were measured using reverse transcription quantitative PCR (RT-qPCR). The Fe2+ and malondialdehyde (MDA) contents were detected with commercial kits. The reactive oxygen species (ROS) production was analyzed via flow cytometry. The integrity of the intestinal epithelium was evaluated using a fluorescein isothiocyanate (FITC)-dextran permeability assay and transepithelial electrical resistance (TEER) measurements.
Results: Bioinformatics identified TIMP1 and PGRMC1 as core genes related to ferroptosis of UC. Both TIMP1 and PGRMC1 were upregulated in colonic biopsies from UC patients in the GSE87466 dataset. The mRNA expression was induced after LPS treatment, whereas PGRMC1 was not significantly altered. TIMP1 knockdown inhibited the expression of IL-1β and IL-6; reduced Fe2+, MDA, and ROS levels; and upregulated the…
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