{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T06:08:12Z","timestamp":1788761292897,"version":"build-2803163510"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"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:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Tubulointerstitial fibrosis (TIF) is a major pathological feature of progressive chronic kidney disease (CKD), yet effective pharmacological therapies remain limited. Bruceine A (BA), a quassinoid isolated from\n                      <jats:italic>Brucea javanica<\/jats:italic>\n                      , has been reported to exert renoprotective effects in glomerular diseases. However, its pharmacological role in renal TIF and the underlying mechanisms remain poorly defined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we investigated the effects of BA in two classic animal models of TIF, unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (UIRI), as well as in TGF-\u03b21-stimulated HK-2 cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>BA significantly attenuated renal histopathological injury, inflammatory responses, and fibrotic changes in both in vivo models, and improved renal function in UIRI mice. BA dose-dependently suppressed TGF-\u03b21-induced epithelial-mesenchymal transition (EMT) and fibrotic responses in HK-2 cells. Mechanistically, RNA sequencing identified Wnt7a as a BA-responsive gene in fibrotic kidneys. BA consistently reduced Wnt7a expression in vivo and in vitro, while integrated RNA-seq and network pharmacology analyses implicated PI3K\/AKT signaling as a key downstream pathway, which was further supported by reduced PI3K and AKT phosphorylation after BA treatment. Moreover, recombinant Wnt7a protein and the AKT agonist SC79 partially reversed BA-mediated suppression of fibrotic marker expression in HK-2 cells. Recombinant Wnt7a also partially restored PI3K\/AKT activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Collectively, these findings suggest that BA attenuates renal tubulointerstitial injury and fibrosis, potentially through modulation of the Wnt7a\/PI3K\/AKT signaling pathway, supporting its potential as a therapeutic candidate for TIF.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1865261","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T05:33:21Z","timestamp":1788759201000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Bruceine A attenuates renal tubulointerstitial fibrosis by inhibiting the Wnt7a\/PI3K\/AKT pathway"],"prefix":"10.3389","volume":"17","author":[{"given":"Shuangyu","family":"Li","sequence":"first","affiliation":[{"name":"Department of Anatomy, School of Basic Medicine, Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renqing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, The First Affiliated Hospital of Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Basic Medicine, Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Basic Medicine, Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengchun","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Basic Medicine, Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Basic Medicine, Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renfei","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Basic Medicine, Anhui Medical University","place":["Hefei, Anhui, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1681\/ASN.0000000000000328","article-title":"WWP2 regulates renal fibrosis and the metabolic reprogramming of profibrotic myofibroblasts","volume":"35","author":"Chen","year":"2024","journal-title":"J. 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