2. Academic Validation
  3. FATS alleviates ulcerative colitis by inhibiting M1 macrophage polarization and aerobic glycolysis through promoting the ubiquitination-mediated degradation of HIF-1α

FATS alleviates ulcerative colitis by inhibiting M1 macrophage polarization and aerobic glycolysis through promoting the ubiquitination-mediated degradation of HIF-1α

  • Biochem Pharmacol. 2025 Jun 19:240:117053. doi: 10.1016/j.bcp.2025.117053.
Yingdi Han 1,  Jing Xun 1,  Tian Li 1,  Xiaolin Jiang 1,  Bin Liu 1,  Zhibo Hu 1,  Huichao Yang 1,  Qi Gao 1,  Zhao Wu 1,  Xueliang Wu 2,  Aimin Zhang 3,  Ximo Wang 4,  Zhiyu Guan 5,  Xiangyang Yu 6,  Qi Zhang 7
Affiliations

Affiliations

  • 1 Tianjin Nankai Hospital, Tianjin Medical University, 300110 Tianjin, China; Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, 300110 Tianjin, China; Institute of Integrative Medicine for Acute Abdominal Diseases, 300110 Tianjin, China.
  • 2 Department of General Surgery, The First Affiliated Hospital of Hebei North University, 075000 Hebei, China.
  • 3 Tianjin Nankai Hospital, Tianjin Medical University, 300110 Tianjin, China.
  • 4 Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, 300110 Tianjin, China; Institute of Integrative Medicine for Acute Abdominal Diseases, 300110 Tianjin, China.
  • 5 School of Basic Medicine, Shandong Second Medical University, 261000 Shandong, China.
  • 6 Tianjin Nankai Hospital, Tianjin Medical University, 300110 Tianjin, China; Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, 300110 Tianjin, China; Institute of Integrative Medicine for Acute Abdominal Diseases, 300110 Tianjin, China. Electronic address: yxynankai@126.com.
  • 7 Tianjin Nankai Hospital, Tianjin Medical University, 300110 Tianjin, China; Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, 300110 Tianjin, China; Institute of Integrative Medicine for Acute Abdominal Diseases, 300110 Tianjin, China. Electronic address: zhangqi@tmu.edu.cn.
PMID: 40543763 DOI: 10.1016/j.bcp.2025.117053
Abstract

Ulcerative colitis (UC) represents a challenging disorder characterized by a multifaceted pathogenesis. Macrophages, the predominant immune cell population in the intestinal milieu of individuals with UC, play a pivotal role in sustaining intestinal homeostasis. Common fragile sites (CFSs) are evolutionarily preserved genomic segments that exhibit a propensity for breakage and are present in all human beings. FATS (fragile site-associated tumor suppressor) is a novel CFS that functions as a tumor suppressor gene and an E3 ubiquitin Ligase. But there are no studies on the regulation of inflammatory diseases by this gene. In this study, we used Fats whole-body knockout mice to construct DSS-induced UC model and elucidate the role of Fats in the progression of UC through immune regulation. We found that UC was more severe in Fats-/- mice than in WT control mice. The aggravation of UC observed in Fats-/- mice is contingent upon macrophage activity and corresponds with a phenotypic transition in colonic macrophages from an anti-inflammatory M2-like state to a pro-inflammatory M1-like state. In addition, co-IP (co-immunoprecipitation), PLA (Proximity ligation assay) and ubiquitylation experiments confirmed that Fats deficiency stabilizes the HIF-1α protein by reducing its degree of ubiquitination, which in turn heightens the expression of the transporters GLUT1 and the Enzymes Hk2 (Hexokinase 2) and Ldha (Lactate Dehydrogenase) during glycolysis, thereby fostering macrophage polarization towards the M1 phenotype and exacerbating UC. Notably, inhibition of HIF-1α expression reversed the exacerbation of UC in Fats-/- mice. Collectively, these findings indicate that Fats plays a crucial role in modulating immune responses, positioning it as a potential therapeutic target in UC management.

Keywords

Fats; Glycolysis; Macrophage; Ubiquitination; Ulcerative colitis.

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