AUTHOR=Guo Xiao-Xiao , Chang Xue-Jiao , Pu Qi , Li Ao-Ling , Li Jing , Li Xin-Yu 

TITLE=Urolithin A alleviates cell senescence by inhibiting ferroptosis and enhances corneal epithelial wound healing

JOURNAL=Frontiers in Medicine

VOLUME=11

YEAR=2024

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1441196

DOI=10.3389/fmed.2024.1441196

ISSN=2296-858X

ABSTRACT=<sec id="sec1"><title>Purpose</title><p>To analyze the therapeutic effect and mechanism of Urolithin A (UA) on delayed corneal epithelial wound healing.</p></sec><sec id="sec2"><title>Methods</title><p>The C57BL/6 mice were continuously exposed to hyperosmotic stress (HS) for 7 days followed by the removal of central corneal epithelium to establish a delayed corneal epithelial wound healing model <italic>in vivo</italic>. <italic>In vitro</italic>, the human corneal epithelial cell line (HCE-T) was also incubated under HS. UA was administered <italic>in vivo</italic> and <italic>in vitro</italic> to study its effects on corneal epithelial cells. Senescence-associated β-galactosidase (SA-β-gal) staining was performed to detect the level of cell senescence. Transcriptome sequencing (RNA-seq) was conducted to elucidate the molecular mechanism underlying the effect of UA on corneal epithelial repair. Additionally, the expression of senescence-related and ferroptosis-related genes and the levels of lipid peroxides (LPO) and malondialdehyde (MDA) were measured.</p></sec><sec id="sec3"><title>Results</title><p>Hyperosmotic stress (HS) significantly increased the proportion of SA-β-gal staining positive cells in corneal epithelial cells and upregulated the expression of p16 and p21 (<italic>p</italic> &lt; 0.0001). Topical application of UA decreased the accumulation of senescent cells in corneal epithelial wounds and promoted epithelial wound healing. The results of RNA-seq of HS-induced corneal epithelial cells showed that the ferroptosis pathway was significantly dysregulated. Further investigation revealed that UA decreased the level of oxidative stress in HCE-T cells, including the levels of LPO and MDA (<italic>p</italic> &lt; 0.05). Inhibition of ferroptosis significantly prevented cellular senescence in HS-induced HCE-T cells.</p></sec><sec id="sec4"><title>Conclusion</title><p>In this study, UA promoted HS-induced delayed epithelial wound healing by reducing the senescence of corneal epithelial cells through the inhibition of ferroptosis.</p></sec>