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

Moo Hyun Kim¹, Yongdae Yoon², Chang Wan Kim¹, Jun-Won Lee³, Bhupendra Regmi², Saher Fatima², Moon Young Kim^2,3, Soon Koo Baik^2,3, Pil Young Jung^1,*, Young Woo Eom^2,*
1 Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
2 Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
3 Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
* Corresponding Author: Pil Young Jung. Email: email ; Young Woo Eom. Email: email

BIOCELL https://doi.org/10.32604/biocell.2026.076364

Received 19 November 2025; Accepted 04 March 2026; Published online 13 March 2026

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Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.