@Article{biocell.2026.076364,
AUTHOR = {Moo Hyun Kim, Yongdae Yoon, Chang Wan Kim, Jun-Won Lee, Bhupendra Regmi, Saher Fatima, Moon Young Kim, Soon Koo Baik, Pil Young Jung, Young Woo Eom},
TITLE = {12-O-Tetradecanoylphorbol-13-Acetate Inhibits TGF-β1-Induced Proliferation and Fibrosis in LX-2 Hepatic Stellate Cells by Regulating both YAP and AKT Activities},
JOURNAL = {BIOCELL},
VOLUME = {},
YEAR = {},
NUMBER = {},
PAGES = {{pages}},
URL = {http://www.techscience.com/biocell/online/detail/26216},
ISSN = {1667-5746},
ABSTRACT = {<b>Background:</b> Although transforming growth factor-β (TGF-β) drives hepatic stellate cell activation and fibrogenesis, the mechanisms by which 12-O-tetradecanoylphorbol-13-acetate (TPA) modulates these processes in TGF-β1-activated hepatic stellate cells remain to be determined. Therefore, we investigated whether TPA alleviates fibrosis in TGF-β1-treated hepatic stellate cells and regulates both canonical and non-canonical pathways. Further, we assessed whether inhibitors of these pathways similarly affect proliferation and fibrosis in LX-2 cells. <b>Methods:</b> LX-2 hepatic stellate cells were used as the experimental model. Cells were treated with TPA, TGF-β, or TGF-β plus TPA, and Yes-associated protein (YAP) and protein kinase B (PKB; AKT) phosphorylation, as well as YAP intracellular localization, were assessed. PKC-δ involvement was examined using the pan-PKC inhibitor Go 6983, and the roles of YAP and AKT in TGF-β1-activated LX-2 cells were evaluated using verteporfin and AKTI-1/2, respectively. <b>Results:</b> TPA significantly increased YAP phosphorylation and reduced its nuclear translocation, resulting in decreased LX-2 cell proliferation and fibronectin (FN1) production. Although TPA also inhibited AKT phosphorylation, FN1 expression was primarily regulated by YAP inhibition. Notably, proliferation in TGF-β1-treated LX-2 cells was suppressed only upon co-administration of both inhibitors. Our results suggest that coordinated regulation of YAP and AKT activity is essential for controlling fibroblast proliferation and ECM production. <b>Conclusions:</b> These findings suggest that in TGF-β-activated hepatic stellate cells, YAP simultaneously controls proliferation and fibrosis, and AKT regulates only proliferation. Therefore, TPA, which regulates both YAP and AKT activity, may be a promising therapeutic candidate for liver fibrosis treatment by simultaneously controlling proliferation and fibrosis in hepatic stellate cells.},
DOI = {10.32604/biocell.2026.076364}
}