Journal of clinical and translational hepatology · 2026
Palmatine Induces TNNT1 Ubiquitination and Degradation to Potentiate Ferroptosis Sensitivity in Hepatocellular Carcinoma.
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Wang Xiaokang, Xie Fanci, Wang Chunhua, Zhou Shangjun, Wang Jiayu, Xu Zhijie, Zhou Zhiyang
Аннотация
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 hepatocellular carcinoma (HCC).
METHODS: An alkaloid library was used to screen alkaloids with anti-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: This study reveals a previously unrecognized role of PAL as a ferroptosis sensitizer and highlights its translational potential for anti-HCC therapy.
METHODS: An alkaloid library was used to screen alkaloids with anti-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: This study reveals a previously unrecognized role of PAL as a ferroptosis sensitizer and highlights its translational potential for anti-HCC therapy.