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<p><i>Background</i> Liquid-liquid phase separation (LLPS) has emerged as an important regulatory mechanism in cancer biology and has been implicated in hepatocellular carcinoma (HCC) progression. LLPS has also been linked to ferroptosis, a regulated cell death process with tumor-suppressive potential. However, how LLPS-related regulators modulate ferroptosis in HCC remain unclear. Here, we report the precise mechanism of TRIM21 in regulating the susceptibility of HCC to ferroptosis. <i>Methods</i> Bioinformatics analysis was employed to evaluate TRIM21 expression in HCC and identify ferroptosis suppressors potentially associated with TRIM21. In vitro experiments were then conducted to assess the impact of TRIM21 on cell malignant phenotypes. Finally, immunofluorescence and FRAP experiments were carried out to investigate the phase separation phenomenon of TRIM21. <i>Results</i> TRIM21 was found to be upregulated in HCC and associated with prognosis. Bioinformatic screening identified EZH2 as a candidate ferroptosis suppressor associated with TRIM21. TRIM21 knockdown enhanced ferroptosis sensitivity in HCC cells and suppressed malignant phenotypes. Mechanistically, TRIM21 underwent LLPS that depended on its coiled-coil domain (a predicted IDR region). Co-immunoprecipitation assays and immunofluorescence further supported a molecular association between TRIM21 and EZH2. Disruption of LLPS by TRIM21 mutant effectively abolished its cytoplasmic colocalization with EZH2, thereby attenuating the invasive capacity of HCC cells. <i>Conclusion</i> This study demonstrates that TRIM21 inhibits ferroptosis through LLPS, thereby promoting HCC cell survival. These findings reveal a previously unrecognized link between TRIM21 LLPS, ferroptosis, and HCC progression, providing a rational basis for targeting LLPS mechanisms to treat HCC.</p>

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Liquid-liquid phase separation of TRIM21 regulates EZH2-mediated ferroptosis to facilitate hepatocellular carcinoma progression

  • 期刊论文

  • 发表日期：

    2026年4月29日

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  • Li Xu,
  • Shilun Wu,
  • Changyu Yao,
  • Shaohong Wang

摘要

Background Liquid-liquid phase separation (LLPS) has emerged as an important regulatory mechanism in cancer biology and has been implicated in hepatocellular carcinoma (HCC) progression. LLPS has also been linked to ferroptosis, a regulated cell death process with tumor-suppressive potential. However, how LLPS-related regulators modulate ferroptosis in HCC remain unclear. Here, we report the precise mechanism of TRIM21 in regulating the susceptibility of HCC to ferroptosis. Methods Bioinformatics analysis was employed to evaluate TRIM21 expression in HCC and identify ferroptosis suppressors potentially associated with TRIM21. In vitro experiments were then conducted to assess the impact of TRIM21 on cell malignant phenotypes. Finally, immunofluorescence and FRAP experiments were carried out to investigate the phase separation phenomenon of TRIM21. Results TRIM21 was found to be upregulated in HCC and associated with prognosis. Bioinformatic screening identified EZH2 as a candidate ferroptosis suppressor associated with TRIM21. TRIM21 knockdown enhanced ferroptosis sensitivity in HCC cells and suppressed malignant phenotypes. Mechanistically, TRIM21 underwent LLPS that depended on its coiled-coil domain (a predicted IDR region). Co-immunoprecipitation assays and immunofluorescence further supported a molecular association between TRIM21 and EZH2. Disruption of LLPS by TRIM21 mutant effectively abolished its cytoplasmic colocalization with EZH2, thereby attenuating the invasive capacity of HCC cells. Conclusion This study demonstrates that TRIM21 inhibits ferroptosis through LLPS, thereby promoting HCC cell survival. These findings reveal a previously unrecognized link between TRIM21 LLPS, ferroptosis, and HCC progression, providing a rational basis for targeting LLPS mechanisms to treat HCC.