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Background <p>Hepatocellular carcinoma (HCC) is still one of the leading causes of cancer-related mortality worldwide. Sorafenib is commonly used as first-line systemic treatment for advanced HCC, but the clinical benefits fall victim to either primary or acquired drug resistance. Modulating ferroptosis, a form of iron-dependent regulated cell death (RCD), has been increasingly explored in order to circumvent this chemoresistance.</p> Methods <p>We performed a pharmacogenomic screening analysis using the DepMap database to identify small molecules whose cytotoxicity patterns resemble those of known ferroptosis inducers. Among the candidates, LDN-57444 was selected for further evaluation. Its ability to enhance the anticancer activity of sorafenib was examined in PLC/PRF/5 and Hep3B HCC cell lines using cell viability assays, molecular docking, cellular thermal shift assays (CETSA), and siRNA-mediated gene silencing.</p> Results <p>In the HCC models tested, sorafenib alone did not induce ferroptosis, unlike some earlier reports. LDN-57444, previously described as an inhibitor of ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), emerged as a strong ferroptosis sensitizer. Co-treatment with LDN-57444 and sorafenib led to pronounced synergistic cytotoxicity, and this effect was completely abolished by the ferroptosis inhibitor ferrostatin-1. Mechanistic analyses showed that the synergy is independent of UCH-L1. Structural modeling and target-engagement experiments indicated that histone deacetylase 2 (HDAC2) is the relevant molecular target. Silencing HDAC2, but not HDAC1, reduced sensitivity to the drug combination, supporting the idea that LDN-57444 enhances sorafenib activity by modulating HDAC2.</p> Conclusion <p>Our findings demonstrate that LDN-57444 potentiates sorafenib-induced ferroptosis in HCC cells through an HDAC2-dependent mechanism. These results highlight the therapeutic potential of combining HDAC2 inhibitors with sorafenib to improve treatment responses in advanced HCC.</p>

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LDN-57444 sensitizes hepatocellular carcinoma cells to sorafenib by promoting ferroptosis through histone deacetylase 2 (HDAC2) inhibition

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月13日

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  • Jiunn-Chang Lin,
  • Tun-Sung Huang,
  • Yan-Bin Chen,
  • Tung-Ying Chen,
  • Pao-Shu Wu,
  • Tsang-Pai Liu,
  • Pei-Ming Yang

摘要

Background

Hepatocellular carcinoma (HCC) is still one of the leading causes of cancer-related mortality worldwide. Sorafenib is commonly used as first-line systemic treatment for advanced HCC, but the clinical benefits fall victim to either primary or acquired drug resistance. Modulating ferroptosis, a form of iron-dependent regulated cell death (RCD), has been increasingly explored in order to circumvent this chemoresistance.

Methods

We performed a pharmacogenomic screening analysis using the DepMap database to identify small molecules whose cytotoxicity patterns resemble those of known ferroptosis inducers. Among the candidates, LDN-57444 was selected for further evaluation. Its ability to enhance the anticancer activity of sorafenib was examined in PLC/PRF/5 and Hep3B HCC cell lines using cell viability assays, molecular docking, cellular thermal shift assays (CETSA), and siRNA-mediated gene silencing.

Results

In the HCC models tested, sorafenib alone did not induce ferroptosis, unlike some earlier reports. LDN-57444, previously described as an inhibitor of ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), emerged as a strong ferroptosis sensitizer. Co-treatment with LDN-57444 and sorafenib led to pronounced synergistic cytotoxicity, and this effect was completely abolished by the ferroptosis inhibitor ferrostatin-1. Mechanistic analyses showed that the synergy is independent of UCH-L1. Structural modeling and target-engagement experiments indicated that histone deacetylase 2 (HDAC2) is the relevant molecular target. Silencing HDAC2, but not HDAC1, reduced sensitivity to the drug combination, supporting the idea that LDN-57444 enhances sorafenib activity by modulating HDAC2.

Conclusion

Our findings demonstrate that LDN-57444 potentiates sorafenib-induced ferroptosis in HCC cells through an HDAC2-dependent mechanism. These results highlight the therapeutic potential of combining HDAC2 inhibitors with sorafenib to improve treatment responses in advanced HCC.