{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T15:53:54Z","timestamp":1782748434759,"version":"3.54.5"},"reference-count":87,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T00:00:00Z","timestamp":1772928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Beijing Natural Science Foundation","award":["7244471"],"award-info":[{"award-number":["7244471"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alpha-2-macroglobulin (\u03b12M) is a conserved plasma glycoprotein traditionally known for its broad-spectrum protease inhibitory activity. However, emerging evidence indicates that its activated form, \u03b12M*, generated via proteolytic cleavage or nucleophilic attack, functions as a versatile signaling ligand. By engaging specific cell-surface receptors, most notably low-density lipoprotein receptor-related protein 1 (LRP1) and glucose-regulated protein 78 (GRP78), \u03b12M* orchestrates a diverse array of intracellular programs, including the PI3K\/Akt\/mTOR, MAPK\/ERK, and JAK\/STAT cascades, as well as mechanosensitive YAP\/TAZ signaling. These pathways collectively govern fundamental cellular processes such as proliferation, metabolic reprogramming, cytoskeletal remodeling, and inflammatory adaptation across various cell types, including macrophages, cardiomyocytes, and malignant cells. Altogether, this review synthesizes current knowledge on \u03b12M activation, structural transitions, receptor interactions, and downstream signaling, highlighting the expanding functional landscape of \u03b12M* as a potent regulator of intracellular communication with implications for physiology and disease.<\/jats:p>","DOI":"10.3390\/ijms27052487","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T10:16:12Z","timestamp":1773051372000},"page":"2487","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Intracellular Signaling Regulated by Activated \u03b12-Macroglobulin: Expanding Beyond Its Protease Inhibitory Role"],"prefix":"10.3390","volume":"27","author":[{"given":"Lin","family":"Liu","sequence":"first","affiliation":[{"name":"NMPA Key Laboratory for Quality Control of Blood Products, Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Yuan","sequence":"additional","affiliation":[{"name":"NMPA Key Laboratory for Quality Control of Blood Products, Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junting","family":"Jia","sequence":"additional","affiliation":[{"name":"NMPA Key Laboratory for Quality Control of Blood Products, Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyuan","family":"Ma","sequence":"additional","affiliation":[{"name":"NMPA Key Laboratory for Quality Control of Blood Products, Academy of Military Medical Sciences, Beijing 100850, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/S0076-6879(76)45055-3","article-title":"Human \u03b12-macroglobulin","volume":"45","author":"Harpel","year":"1976","journal-title":"Methods Enzym."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1515\/znb-1955-0810","article-title":"Zur kenntnis der \u03b1-globuline des menschlichen normalserums","volume":"10","author":"Schultze","year":"1955","journal-title":"Z. 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