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Background <p>Ovarian cancer (OC) remains a leading cause of gynecologic cancer mortality worldwide, highlighting the need for novel immunomodulatory therapies. Immunogenic cell death (ICD) has emerged as a promising strategy to enhance antitumor immunity in OC. Baicalein, a bioactive flavonoid with documented anticancer activity across diverse tumor types, has not been comprehensively assessed for its potential to induce ICD in OC. This study aimed to explore baicalein’s ability to promote ICD and elucidate the underlying molecular mechanisms.</p> Methods <p>Both murine (ID8) and human (SKOV3) ovarian cancer cell lines were used to examine the cytotoxic and immunogenic effects of baicalein. Cell viability and apoptosis were evaluated using CCK-8 assays and flow cytometry. ICD hallmarks, including surface calreticulin (CRT) exposure, extracellular ATP and HMGB1 release, as well as the induction of pro-inflammatory cytokines, were systematically evaluated in cells treated with baicalein. The functional impact on immune activation was assessed in vitro using dendritic cells and in vivo via T cell priming assays. RNA-sequencing and RT-PCR were used to explore underlying molecular pathways, including endoplasmic reticulum (ER) stress signaling and IL-24 induction.</p> Results <p>We found that OC cells treated with baicalein showed increased ICD features, including CRT exposure, extracellular release of ATP and HMGB1, and increased expression of IFNβ and CXCL10. Functionally, baicalein-treated OC cells promoted dendritic cell maturation and stimulated CD4⁺ and CD8⁺ T cell responses in vivo. Transcriptomic analysis revealed activation of ER stress pathways, particularly the ATF3/CHOP/DR5 axis. Inhibition of ER stress or reactive oxygen species (ROS) attenuated baicalein-induced ICD, suggesting a ROS-dependent mechanism. Notably, baicalein markedly upregulated IL-24 expression in an ER stress-dependent manner and IL-24 further enhanced baicalein-induced ER stress and ICD features.</p> Conclusion <p>This study reveals that BAI induces IL-24 expression through ER stress, with IL-24 subsequently reinforcing BAI-mediated ER stress and potentiating ICD in ovarian cancer. These findings support the therapeutic potential of BAI as an ICD inducer and immunomodulatory agent in ovarian cancer.</p>

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IL-24 amplifies baicalein-induced immunogenic cell death in ovarian cancer by boosting endoplasmic reticulum stress

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月8日

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  • Jie Yang,
  • Feima Wu,
  • Biling Zhong,
  • Yexin Liu,
  • Qiao Yuan,
  • Guimin Wang,
  • Jianbin Zhou,
  • Hui Peng

摘要

Background

Ovarian cancer (OC) remains a leading cause of gynecologic cancer mortality worldwide, highlighting the need for novel immunomodulatory therapies. Immunogenic cell death (ICD) has emerged as a promising strategy to enhance antitumor immunity in OC. Baicalein, a bioactive flavonoid with documented anticancer activity across diverse tumor types, has not been comprehensively assessed for its potential to induce ICD in OC. This study aimed to explore baicalein’s ability to promote ICD and elucidate the underlying molecular mechanisms.

Methods

Both murine (ID8) and human (SKOV3) ovarian cancer cell lines were used to examine the cytotoxic and immunogenic effects of baicalein. Cell viability and apoptosis were evaluated using CCK-8 assays and flow cytometry. ICD hallmarks, including surface calreticulin (CRT) exposure, extracellular ATP and HMGB1 release, as well as the induction of pro-inflammatory cytokines, were systematically evaluated in cells treated with baicalein. The functional impact on immune activation was assessed in vitro using dendritic cells and in vivo via T cell priming assays. RNA-sequencing and RT-PCR were used to explore underlying molecular pathways, including endoplasmic reticulum (ER) stress signaling and IL-24 induction.

Results

We found that OC cells treated with baicalein showed increased ICD features, including CRT exposure, extracellular release of ATP and HMGB1, and increased expression of IFNβ and CXCL10. Functionally, baicalein-treated OC cells promoted dendritic cell maturation and stimulated CD4⁺ and CD8⁺ T cell responses in vivo. Transcriptomic analysis revealed activation of ER stress pathways, particularly the ATF3/CHOP/DR5 axis. Inhibition of ER stress or reactive oxygen species (ROS) attenuated baicalein-induced ICD, suggesting a ROS-dependent mechanism. Notably, baicalein markedly upregulated IL-24 expression in an ER stress-dependent manner and IL-24 further enhanced baicalein-induced ER stress and ICD features.

Conclusion

This study reveals that BAI induces IL-24 expression through ER stress, with IL-24 subsequently reinforcing BAI-mediated ER stress and potentiating ICD in ovarian cancer. These findings support the therapeutic potential of BAI as an ICD inducer and immunomodulatory agent in ovarian cancer.