{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T01:19:24Z","timestamp":1788484764872,"version":"build-2803163510"},"reference-count":90,"publisher":"American Society of Hematology","issue":"20","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,5,15]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Hyperhomocysteinemia (HHcy) is strongly associated with cardiovascular diseases (CVDs), and it has been identified as a risk factor for thrombotic diseases. Most patients with HHcy die from various complications closely related to thrombotic diseases. However, the underlying mechanisms have not been fully elucidated. G protein-coupled receptors (GPCRs), the central regulators of the cardiovascular system, primarily control platelet activation. By examining the effects of HHcy on a panel of GPCRs involved in platelet aggregation, we found that HHcy systematically modulated biased GPCR signaling through the inhibition of desensitization by \u03b2-arrestins and the amplification of G protein signals. We further revealed that the N-homocysteinylation of \u03b2-arrestin1\/2 at lysine (K) residues (K294\/K296) disrupted the interaction between \u03b2-arrestins and GPCRs. The aforementioned phenomenon may be universal because HHcy was found to modulate the signaling bias of 9 other randomly selected GPCRs. Moreover, we found that the proinflammatory effects of homocysteine and homocysteine thiolactone were weakened in Arrb2\u2013\/\u2013 mice and that the reintroduction of wild-type but not K296R \u03b2-arrestin2 mutants (in mice) into primary peritoneal macrophages reversed these effects. Notably, in Arrb2K296R mice, HHcy-induced thrombus formation and platelet aggregation were reversed. Our results suggest that a G-biased agonist could be a better choice for disease therapy under HHcy conditions. Collectively, our findings demonstrate that the N-homocysteinylation of \u03b2-arrestin1\/\u03b2-arrestin2 actively modulates the biased property of GPCR signaling, which contributes to the pathophysiology of HHcy-related CVDs and provides insight into the selection of agonists for the treatment of diseases under HHcy conditions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2024025593","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T15:10:36Z","timestamp":1739200236000},"page":"2374-2389","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":14,"title":["N-homocysteinylation of \u03b2-arrestins biases GPCR signaling and promotes platelet activation"],"prefix":"10.1182","volume":"145","author":[{"given":"Lin-Qi","family":"Zhang","sequence":"first","affiliation":[{"name":"1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, 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