{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T06:02:32Z","timestamp":1789970552319,"version":"4.0.1"},"reference-count":126,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>A disintegrin and metalloproteinase 17 (ADAM17) is a membrane-bound sheddase that regulates inflammatory signaling, tissue repair, and fibrotic remodeling by converting cell-surface proteins into soluble forms. Rather than viewing ADAM17 simply as a proinflammatory enzyme, this review frames it as a proteolytic rheostat that dynamically adjusts the balance between membrane-bound and soluble molecular states in the injured liver. Within this framework, apparently opposing effects of ADAM17 can be understood as substrate-, cell-, and disease-stage-dependent consequences of ectodomain shedding. We particularly highlight two independently observed patterns of macrophage receptor-state remodeling: insufficient MerTK shedding may preserve profibrotic MerTK\/ERK\/TGF-\u03b21 signaling, whereas excessive TREM2 shedding may reduce efferocytic capacity and contribute to failed inflammatory resolution. We further discuss how ADAM17-mediated shedding reshapes hepatocyte\u2013macrophage\u2013HSC communication and how soluble shedding products may provide circulating readouts of these processes. This framework suggests that therapeutic strategies should move beyond broad ADAM17 inhibition toward context-, cell-, or substrate-selective modulation that limits pathogenic signaling while preserving inflammation-resolving and tissue-repair functions.<\/jats:p>","DOI":"10.3389\/fphar.2026.1955615","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T05:36:18Z","timestamp":1789968978000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ADAM17 as a proteolytic rheostat linking inflammation, tissue repair, and failure of inflammatory resolution in liver injury and fibrosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaodan","family":"Jiang","sequence":"first","affiliation":[{"name":"Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxin","family":"Ma","sequence":"additional","affiliation":[{"name":"Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhejun","family":"Liu","sequence":"additional","affiliation":[{"name":"Qingdao Municipal Hospital","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1111\/j.1478-3231.2005.01191.x","article-title":"Serum cytokine and soluble cytokine receptor levels in patients with non-alcoholic steatohepatitis","volume":"26","author":"Abiru","year":"2006","journal-title":"Liver Int."},{"key":"B2","doi-asserted-by":"publisher","first-page":"779119","DOI":"10.3389\/fimmu.2021.779119","article-title":"ADAM metalloproteinase domain 17 regulates cholestasis-associated liver injury and sickness behavior development in mice","volume":"12","author":"Almishri","year":"2021","journal-title":"Front. 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