{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T21:25:09Z","timestamp":1792272309369,"version":"4.4.0"},"reference-count":40,"publisher":"World Scientific Pub Co Pte Ltd","issue":"06","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82174100"],"award-info":[{"award-number":["82174100"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Am. J. Chin. Med."],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p> Oxidative stress serves as a driving force for myofibroblast activation in pulmonary fibrosis (PF). As a main enzymatic source of reactive oxygen species (ROS), NADPH oxidase 4 (Nox4) plays a critical role in modulating myofibroblast activation, and has thus emerged as a potential therapeutic target for PF. Tanshinone IIA (Tan-IIA), the most abundant fat-soluble component found in the root and rhizome of Salvia miltiorrhiza Bge., has been demonstrated to suppress ROS-mediated myofibroblast activation by inhibiting Nox4, and thereby ameliorating PF. However, the mechanism through which Tan-IIA regulates Nox4 to prevent myofibroblast activation remains unclear. This study aimed to investigate the protective effects of Tan-IIA against myofibroblast activation in PF, and to elucidate the upstream molecular mechanisms involved in Nox4 regulation. Tan-IIA inhibited myofibroblast activation by reducing extracellular matrix deposition in a mouse model of bleomycin-induced PF. Furthermore, Tan-IIA enhanced the expression of Sestrin2 (Sesn2), while concurrently suppressing Nox4 expression. This effect was verified using an in vitro model of transforming growth factor beta 1 (TGF-\u03b21)-stimulated myofibroblast activation. We further demonstrated that Sesn2 was required for Tan-IIA to act against TGF-\u03b21-induced myofibroblast activation by inhibiting Nox4-mediated oxidative stress. Additionally, both in vitro and in vivo studies revealed that Tan-IIA activates AMP-activated protein kinase (AMPK) and inhibits mammalian target of rapamycin (mTOR) via the upregulation of Sesn2. The findings indicate that Tan-IIA suppresses Nox4 by regulating the Sesn2\/AMPK\/mTOR signaling pathway, which highlights the crucial effect Sesn2 has in modulating Nox4 expression to prevent myofibroblast activation during PF. <\/jats:p>","DOI":"10.1142\/s0192415x25500685","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T09:59:21Z","timestamp":1755683961000},"page":"1845-1863","source":"Crossref","is-referenced-by-count":4,"title":["Tanshinone IIA Inhibits NADPH Oxidase 4 Expression by Regulating Sestrin2-Mediated AMPK\/mTOR Signaling Pathway to Alleviate Myofibroblast Activation in Pulmonary Fibrosis"],"prefix":"10.1142","volume":"53","author":[{"given":"Congying","family":"Guo","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, P. R. China"},{"name":"School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, P. R. 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