@article{Kim2026, 
author = {Moo Hyun Kim and Yongdae Yoon and Chang Wan Kim and Jun-Won Lee and Bhupendra Regmi and Saher Fatima and Moon Young Kim and Soon Koo Baik and Pil Young Jung and 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},
year = {2026},
journal = {BIOCELL},
volume = {50},
number = {6},
pages = {10},
keywords = {12-O-tetradecanoylphorbol-13-acetate, yes-associated protein, protein kinase B, hepatic stellate cell, transforming growth factor-β1},
url = {https://www.sciopen.com/article/10.32604/biocell.2026.076364},
doi = {10.32604/biocell.2026.076364},
abstract = {BackgroundAlthough 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.MethodsLX-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.ResultsTPA 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.ConclusionsThese 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.}
}