Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis
The damage of integrated epithelial epithelium is a key pathogenic factor and closely associated with the recurrence of ulcerative colitis (UC). Here, we reported that vanillic acid (VA) exerted potent therapeutic effects on DSS-induced colitis by restoring intestinal epithelium homeostasis via the...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-04-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661824000720 |
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| author | Jiahui Ni Lijie Zhang Guize Feng Weilian Bao Yirui Wang Yuran Huang Tongqing Chen Jieli Chen Xinyue Cao Keyuan You Sheng Tan Thomas Efferth Hong Li Bo Li Xiaoyan Shen Yan You |
| author_facet | Jiahui Ni Lijie Zhang Guize Feng Weilian Bao Yirui Wang Yuran Huang Tongqing Chen Jieli Chen Xinyue Cao Keyuan You Sheng Tan Thomas Efferth Hong Li Bo Li Xiaoyan Shen Yan You |
| author_sort | Jiahui Ni |
| collection | DOAJ |
| description | The damage of integrated epithelial epithelium is a key pathogenic factor and closely associated with the recurrence of ulcerative colitis (UC). Here, we reported that vanillic acid (VA) exerted potent therapeutic effects on DSS-induced colitis by restoring intestinal epithelium homeostasis via the inhibition of ferroptosis. By the CETSA assay and DARTS assay, we identified carbonic anhydrase IX (CAIX, CA9) as the direct target of VA. The binding of VA to CA9 causes insulin-induced gene-2 (INSIG2) to interact with stromal interaction molecule 1 (STIM1), rather than SREBP cleavage-activating protein (SCAP), leading to the translocation of SCAP-SREBP1 from the endoplasmic reticulum (ER) to the Golgi apparatus for cleavage into mature SREBP1. The activation of SREBP1 induced by VA then significantly facilitated the transcription of stearoyl-CoA desaturase 1 (SCD1) to exert an inhibitory effect on ferroptosis. By inhibiting the excessive death of intestinal epithelial cells caused by ferroptosis, VA effectively preserved the integrity of intestinal barrier and prevented the progression of unresolved inflammation. In conclusion, our study demonstrated that VA could alleviate colitis by restoring intestinal epithelium homeostasis through CA9/STIM1-mediated inhibition of ferroptosis, providing a promising therapeutic candidate for UC. |
| first_indexed | 2024-04-24T19:48:35Z |
| format | Article |
| id | doaj.art-8507d02c76c1467296f753688e1cd59d |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-04-24T19:48:35Z |
| publishDate | 2024-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-8507d02c76c1467296f753688e1cd59d2024-03-25T04:17:13ZengElsevierPharmacological Research1096-11862024-04-01202107128Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosisJiahui Ni0Lijie Zhang1Guize Feng2Weilian Bao3Yirui Wang4Yuran Huang5Tongqing Chen6Jieli Chen7Xinyue Cao8Keyuan You9Sheng Tan10Thomas Efferth11Hong Li12Bo Li13Xiaoyan Shen14Yan You15Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, ChinaDepartment of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, ChinaDepartment of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, ChinaDepartment of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, ChinaArtificial Intelligence Innovation and Incubation (AI³) Institute, Fudan University, Shanghai, ChinaDepartment of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, ChinaDepartment of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, ChinaDepartment of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, ChinaDepartment of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, ChinaDepartment of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, ChinaDepartment of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, ChinaDepartment of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, Mainz 55128, GermanyDepartment of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, ChinaAmway (Shanghai) Innovation & Science Center, 720 Cailun Road, Shanghai, China; Corresponding authors.Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China; Shanghai Fifth People's Hospital, Fudan University, Shanghai, China; Artificial Intelligence Innovation and Incubation (AI³) Institute, Fudan University, Shanghai, China; Corresponding author at: Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China.Department of Pharmacology & the Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, China; Corresponding authors.The damage of integrated epithelial epithelium is a key pathogenic factor and closely associated with the recurrence of ulcerative colitis (UC). Here, we reported that vanillic acid (VA) exerted potent therapeutic effects on DSS-induced colitis by restoring intestinal epithelium homeostasis via the inhibition of ferroptosis. By the CETSA assay and DARTS assay, we identified carbonic anhydrase IX (CAIX, CA9) as the direct target of VA. The binding of VA to CA9 causes insulin-induced gene-2 (INSIG2) to interact with stromal interaction molecule 1 (STIM1), rather than SREBP cleavage-activating protein (SCAP), leading to the translocation of SCAP-SREBP1 from the endoplasmic reticulum (ER) to the Golgi apparatus for cleavage into mature SREBP1. The activation of SREBP1 induced by VA then significantly facilitated the transcription of stearoyl-CoA desaturase 1 (SCD1) to exert an inhibitory effect on ferroptosis. By inhibiting the excessive death of intestinal epithelial cells caused by ferroptosis, VA effectively preserved the integrity of intestinal barrier and prevented the progression of unresolved inflammation. In conclusion, our study demonstrated that VA could alleviate colitis by restoring intestinal epithelium homeostasis through CA9/STIM1-mediated inhibition of ferroptosis, providing a promising therapeutic candidate for UC.http://www.sciencedirect.com/science/article/pii/S1043661824000720UCFerroptosisCA9(CAIX)INSIG2Vanillic acid |
| spellingShingle | Jiahui Ni Lijie Zhang Guize Feng Weilian Bao Yirui Wang Yuran Huang Tongqing Chen Jieli Chen Xinyue Cao Keyuan You Sheng Tan Thomas Efferth Hong Li Bo Li Xiaoyan Shen Yan You Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis Pharmacological Research UC Ferroptosis CA9(CAIX) INSIG2 Vanillic acid |
| title | Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis |
| title_full | Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis |
| title_fullStr | Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis |
| title_full_unstemmed | Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis |
| title_short | Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis |
| title_sort | vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting ca9 stim1 mediated ferroptosis |
| topic | UC Ferroptosis CA9(CAIX) INSIG2 Vanillic acid |
| url | http://www.sciencedirect.com/science/article/pii/S1043661824000720 |
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