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This study aims to profile the ubiquitinome of the human hypothalamus, uncovering the ubiquitylation landscape and its potential implications in hypothalamic function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Design<\/jats:title>\n                    <jats:p>We employed LC\u2012MS\/MS to analyze hypothalamic tissues from six healthy elderly individuals, focusing on identifying and characterizing ubiquitinated sites and proteins. Motif analysis, functional enrichment, and protein\u2013protein interaction (PPI) network were conducted to profile the landscape.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our analysis identified 21,815 ubiquitinated sites across 5314 proteins and five types of modification motifs in the normal human hypothalamus. Ubiquitinated proteins were predominantly localized to the cell membrane. Functional enrichment related to neuronal and endocrine pathways, especially with MAPK signaling. PPI network analysis focused on five ubiquitinated proteins, including PRKACA, PRKACB, PRKCA, PRKCB, and PRKCG. Additionally, we analyzed their relationship with E3 ligases using UbiBrowser.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Clinical Relevance<\/jats:title>\n                    <jats:p>This study offers the first comprehensive analysis of the human hypothalamic ubiquitinome. Our work provides a reliable foundation for future research into the implications of ubiquitylation in neuroendocrine\u2010related disorders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Summary<\/jats:title>\n                    <jats:p>The human hypothalamus is crucial in regulating metabolism, stress response, and circadian rhythms. Dysfunctions in these processes are linked to various disorders, including Alzheimer's disease, obesity, and sleep disorders. Although ubiquitylation is a key protein modification that affects cellular function, its specific role within the hypothalamus remains poorly understood.<\/jats:p>\n                    <jats:p>This study provides the first detailed profile of lysine ubiquitylation in the human hypothalamus, identifying over 21,000 ubiquitinated sites on more than 5000 proteins. The findings provide valuable insights into the ubiquitylation landscape, highlighting key ubiquitinated proteins and pathways that may be involved in neuroendocrine diseases.<\/jats:p>\n                    <jats:p>This research provides a foundation\u00a0for future research and highlights the potential of ubiquitylation as a therapeutic target for neurological and endocrine disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/prca.70029","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T05:45:42Z","timestamp":1762753542000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Global Profiling of Lysine Ubiquitylation in the Human Hypothalamus"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4724-7150","authenticated-orcid":false,"given":"Zhi\u2010Yi","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases Department of Biochemistry and Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences School of Basic Medicine Peking Union Medical College  Beijing China"},{"name":"School of Basic Medical Science Guizhou Medical University  Guiyang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9808-0912","authenticated-orcid":false,"given":"Tao","family":"Ding","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases Department of Biochemistry and Molecular Biology Institute of Basic Medical Sciences Chinese Academy of Medical Sciences School of Basic Medicine Peking Union Medical College  Beijing China"},{"name":"School of Basic Medical Science Guizhou Medical University  Guiyang 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