Excessive ultra-processed foods exposure aggravates ulcerative colitis via macrophage ferroptosis
Ulcerative colitis (UC), a chronic inflammatory disease with global prevalence, is increasingly associated with environmental exposure to modern dietary hazards, particularly ultra-processed foods (UPFs) containing oxidized phytosterols. While industrial food processing techniques and repeated oil r...
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Elsevier
2025-08-01
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| Series: | Environment International |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S016041202500457X |
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| author | Xiaoqi Pang Jing Yan Xinrui Lv Jingjing Wang Qi Chen Yaxin Qi Xin Xu Bangmao Wang Hailong Cao |
| author_facet | Xiaoqi Pang Jing Yan Xinrui Lv Jingjing Wang Qi Chen Yaxin Qi Xin Xu Bangmao Wang Hailong Cao |
| author_sort | Xiaoqi Pang |
| collection | DOAJ |
| description | Ulcerative colitis (UC), a chronic inflammatory disease with global prevalence, is increasingly associated with environmental exposure to modern dietary hazards, particularly ultra-processed foods (UPFs) containing oxidized phytosterols. While industrial food processing techniques and repeated oil reuse are known to amplify formation of phytosterol oxidation products, their biological impacts on intestinal inflammation remain unexplored. This study focuses on 7-ketositosterol (KS), the most abundant phytosterol oxide found in UPFs, and its role in UC. Clinically, dietary analysis revealed a positive correlation between KS intake and Mayo score in UC patients (p < 0.01). Furthermore, in a C57BL/6 mouse model, KS was demonstrated to exacerbate dextran sulfate sodium (DSS)-induced colitis (p < 0.001). Mechanistically, KS impedes nuclear translocation of the N⁶-methyladenosine (m⁶A) demethylase AlkB homolog 5 (ALKBH5) (p < 0.05). This suppression downregulates expression of the glutamate-cysteine ligase modifier subunit (GCLM), impairing glutathione biosynthesis and ultimately triggering macrophage ferroptosis, as evidenced by increased levels of malondialdehyde (MDA), Fe2+, and reactive oxygen species (ROS) with statistical significance (p < 0.05). Crucially, ALKBH5 overexpression restored GCLM-mediated antioxidant defenses and mitigated ferroptosis in RAW264.7 cells (p < 0.05). Immunofluorescence confirmed KS-mediated suppression of the ALKBH5-GCLM axis in clinical specimens, exhibiting strong correlation with UC (p < 0.05). Our findings establish UPFs-derived KS as a novel environmental driver of UC pathogenesis through regulation of macrophage ferroptosis. These results identify the KS-ALKBH5-GCLM-ferroptosis axis as a promising therapeutic target for UC intervention. |
| format | Article |
| id | doaj-art-7a473c84841e49119b3b4c377b32fb45 |
| institution | Kabale University |
| issn | 0160-4120 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
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| series | Environment International |
| spelling | doaj-art-7a473c84841e49119b3b4c377b32fb452025-08-20T03:58:11ZengElsevierEnvironment International0160-41202025-08-0120210970610.1016/j.envint.2025.109706Excessive ultra-processed foods exposure aggravates ulcerative colitis via macrophage ferroptosisXiaoqi Pang0Jing Yan1Xinrui Lv2Jingjing Wang3Qi Chen4Yaxin Qi5Xin Xu6Bangmao Wang7Hailong Cao8Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, ChinaDepartment of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China; Department of Nutrition, the Second Affiliated Hospital, Air Force Medical University, Xi’an 710038, ChinaDepartment of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, ChinaDepartment of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China; Department of Nutrition, the Third Central Hospital of Tianjin, Tianjin 300170, ChinaDepartment of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, ChinaDepartment of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, ChinaDepartment of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, ChinaDepartment of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China; Corresponding author at: Anshan Road No. 154, Heping District, Tianjin 300052, China.Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China; Corresponding author at: Anshan Road No. 154, Heping District, Tianjin 300052, China.Ulcerative colitis (UC), a chronic inflammatory disease with global prevalence, is increasingly associated with environmental exposure to modern dietary hazards, particularly ultra-processed foods (UPFs) containing oxidized phytosterols. While industrial food processing techniques and repeated oil reuse are known to amplify formation of phytosterol oxidation products, their biological impacts on intestinal inflammation remain unexplored. This study focuses on 7-ketositosterol (KS), the most abundant phytosterol oxide found in UPFs, and its role in UC. Clinically, dietary analysis revealed a positive correlation between KS intake and Mayo score in UC patients (p < 0.01). Furthermore, in a C57BL/6 mouse model, KS was demonstrated to exacerbate dextran sulfate sodium (DSS)-induced colitis (p < 0.001). Mechanistically, KS impedes nuclear translocation of the N⁶-methyladenosine (m⁶A) demethylase AlkB homolog 5 (ALKBH5) (p < 0.05). This suppression downregulates expression of the glutamate-cysteine ligase modifier subunit (GCLM), impairing glutathione biosynthesis and ultimately triggering macrophage ferroptosis, as evidenced by increased levels of malondialdehyde (MDA), Fe2+, and reactive oxygen species (ROS) with statistical significance (p < 0.05). Crucially, ALKBH5 overexpression restored GCLM-mediated antioxidant defenses and mitigated ferroptosis in RAW264.7 cells (p < 0.05). Immunofluorescence confirmed KS-mediated suppression of the ALKBH5-GCLM axis in clinical specimens, exhibiting strong correlation with UC (p < 0.05). Our findings establish UPFs-derived KS as a novel environmental driver of UC pathogenesis through regulation of macrophage ferroptosis. These results identify the KS-ALKBH5-GCLM-ferroptosis axis as a promising therapeutic target for UC intervention.http://www.sciencedirect.com/science/article/pii/S016041202500457X7-KetositosterolFerroptosisMacrophagesUlcerative colitisUltra-processed foods |
| spellingShingle | Xiaoqi Pang Jing Yan Xinrui Lv Jingjing Wang Qi Chen Yaxin Qi Xin Xu Bangmao Wang Hailong Cao Excessive ultra-processed foods exposure aggravates ulcerative colitis via macrophage ferroptosis Environment International 7-Ketositosterol Ferroptosis Macrophages Ulcerative colitis Ultra-processed foods |
| title | Excessive ultra-processed foods exposure aggravates ulcerative colitis via macrophage ferroptosis |
| title_full | Excessive ultra-processed foods exposure aggravates ulcerative colitis via macrophage ferroptosis |
| title_fullStr | Excessive ultra-processed foods exposure aggravates ulcerative colitis via macrophage ferroptosis |
| title_full_unstemmed | Excessive ultra-processed foods exposure aggravates ulcerative colitis via macrophage ferroptosis |
| title_short | Excessive ultra-processed foods exposure aggravates ulcerative colitis via macrophage ferroptosis |
| title_sort | excessive ultra processed foods exposure aggravates ulcerative colitis via macrophage ferroptosis |
| topic | 7-Ketositosterol Ferroptosis Macrophages Ulcerative colitis Ultra-processed foods |
| url | http://www.sciencedirect.com/science/article/pii/S016041202500457X |
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