TY  - JOUR
T1  - Palmatine Induces TNNT1 Ubiquitination and Degradation to Potentiate Ferroptosis Sensitivity in Hepatocellular Carcinoma 
AU  - Wang, Xiaokang
AU  - Xie, Fanci
AU  - Wang, Chunhua
AU  - Zhou, Shangjun
AU  - Wang, Jiayu
AU  - Xu, Zhijie
AU  - Zhou, Zhiyang
JF  - Journal of Clinical and Translational Hepatology
VL  - 
IS  - 000
SN  - 2310-8819
SP  - 
EP  - 
Y1  - 2026-08-19
DO  - 10.14218/JCTH.2026.00215
UR  - https://www.xiahepublishing.com/2310-8819/JCTH-2026-00215
AB  - Background and Aims 
Ferroptosis, an iron-dependent form of regulated cell death, serves as an important mechanism associated with cancer progression. Natural compounds, particularly alkaloids, have emerged as attractive candidates for regulating ferroptotic cell death, thereby providing a promising anticancer strategy. However, the molecular mechanisms underlying their antitumor effects remain poorly understood. In this study, we aimed to investigate the antitumor effects and underlying mechanisms of natural alkaloids against HCC.
Methods
An alkaloid library was used to screen alkaloids with anti-hepatocellular carcinoma (HCC) activity. A combination of proteomic profiling, in vitro functional assays, and in vivo animal experiments was performed to explore the biological roles and molecular mechanisms of the lead compound.
Results
Through high-throughput screening of an alkaloid library, we identified palmatine (PAL), an active component isolated from Fibraurea recisa Pierre, as a potential ferroptosis sensitizer in HCC cells. PAL treatment triggered typical ferroptotic features in HCC cells, including elevated ferrous iron, reactive oxygen species, and lipid peroxidation, along with decreased glutathione levels. Importantly, the pro-ferroptotic effect of PAL was significantly abolished by two ferroptosis inhibitors, ferrostatin-1 and deferoxamine. Mechanistically, PAL directly interacted with troponin T1 (TNNT1) to trigger its K48-linked polyubiquitination and subsequent protein degradation. Ectopic TNNT1 overexpression significantly rescued PAL-mediated ferroptosis and abrogated its tumor-suppressive effects. In vivo animal models further confirmed that PAL suppressed tumor growth by downregulating TNNT1, with a favorable safety profile.
Conclusions
Therefore, this study reveals a previously unrecognized role of PAL as a ferroptosis sensitizer and highlights its translational potential for anti-HCC therapy.