{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTRIM65 functions as a critical E3 ubiquitin ligase that modulates key innate immune responses and inflammatory processes. It promotes antiviral immunity by interacting with the cytoplasmic RNA sensor MDA5 and catalyzing its K63‐linked ubiquitination at a specific lysine residue, a modification essential for MDA5 oligomerization and subsequent type I interferon production during viral challenge. In parallel, TRIM65 restrains NLRP3 inflammasome activation by binding to the NACHT domain of NLRP3, thereby mediating both K48‐ and K63-linked ubiquitination that disrupts the NEK7–NLRP3 interaction and ultimately limits caspase-1 activation and interleukin-1β secretion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cardiovascular contexts, TRIM65 plays a protective role against pathological cardiac hypertrophy. Studies indicate that it attenuates isoproterenol-induced myocardial hypertrophy and fibrosis by enhancing mitochondrial density and function through the Jak1/Stat1 signaling axis, thereby reducing mitochondria-dependent apoptosis and autophagy. Additionally, in vascular endothelial cells, TRIM65 interacts with VCAM-1 to modulate endothelial inflammation—a process that is pivotal in the development of atherosclerosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these roles, TRIM65 also contributes to tissue protection and tumor biology. In the setting of intestinal ischemia-reperfusion injury, TRIM65 mediates the K48-linked ubiquitination and degradation of TOX4, thereby inhibiting the excessive apoptosis of intestinal epithelial cells and mitigating tissue damage. Moreover, emerging evidence suggests that TRIM65 can influence the tumor microenvironment by regulating interactions between hepatocellular carcinoma cells and tumor-associated macrophages, thus impacting tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Xueting Lang, Tiantian Tang, Tengchuan Jin, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "The E3 Ubiquitin Ligase TRIM65 Negatively Regulates Inflammasome Activation Through Promoting Ubiquitination of NLRP3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Immunol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fimmu.2021.741839"}], "href": "https://doi.org/10.3389/fimmu.2021.741839"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34512673"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34512673"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "HuiTing Liu, ZhiXiang Zhou, HuaNian Deng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Trim65 attenuates isoproterenol-induced cardiac hypertrophy by promoting autophagy and ameliorating mitochondrial dysfunction via the Jak1/Stat1 signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Pharmacol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejphar.2023.175735"}], "href": "https://doi.org/10.1016/j.ejphar.2023.175735"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37080331"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37080331"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xiao-Feng Ma, Yi-Ren Zhou, Zhi-Xiang Zhou, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "E3 ligase TRIM65 alleviates intestinal ischemia/reperfusion injury through inhibition of TOX4-mediated apoptosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-023-06410-x"}], "href": "https://doi.org/10.1038/s41419-023-06410-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38212319"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38212319"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Meixiu Jiang, Dan Wang, Ning Su, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TRIM65 knockout inhibits the development of HCC by polarization tumor-associated macrophages towards M1 phenotype via JAK1/STAT1 signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int Immunopharmacol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.intimp.2024.111494"}], "href": "https://doi.org/10.1016/j.intimp.2024.111494"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38218012"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38218012"}]}]}]}