Scholarlink

Background <p>Chemoresistance to platinum-based agents like cisplatin is a major therapeutic challenge in advanced oral squamous cell carcinoma (OSCC), with 70–80% of recurrent cases developing resistance that severely compromises clinical outcomes. The mechanism of cisplatin resistance still remains unclear and requires further investigation. This study investigated ferroptosis suppression as a mechanism underlying this resistance and explored the therapeutic potential of the histone deacetylase (HDAC) inhibitor sodium butyrate (NaB).</p> Methods <p>Cisplatin-resistant OSCC cells (CAL27/CDDP) and parental cells (CAL27) were used to assess ferroptosis levels and resistance mechanisms. The effects of NaB on reversing cisplatin resistance and inhibiting malignant behaviors (proliferation, migration, invasion) were evaluated in vitro. Mechanistic studies, including identification of key regulators and epigenetic modifications were conducted. The therapeutic effect was further validated in vivo using xenograft tumor models treated with NaB and cisplatin.</p> Results <p>CAL27/CDDP exhibited significant ferroptosis suppression compared to CAL27. NaB effectively reversed cisplatin resistance and inhibited malignant behaviors in both cell lines. Mechanistic exploration revealed that NaB enhanced acetylation at the promoter region of early growth response protein 1 (EGR1) through HDAC9 inhibition, elevating its transcriptional activity. EGR1 functioned as a transcription factor to upregulate cytochrome P450 oxidoreductase (POR) expression, potentiating ferroptosis execution. In vivo experiments further confirmed the therapeutic relevance of this HDAC9/EGR1/POR signaling pathway, as NaB administration significantly sensitized xenograft tumors to cisplatin treatment.</p> Conclusions <p>These findings position NaB as a promising epigenetic modulator for overcoming cisplatin resistance in OSCC models, with immediate clinical implications. The identified pathway offers a redox biology-based therapeutic strategy that could be extended to other chemotherapy-resistant solid tumors, potentially revolutionizing the treatment paradigm for recurrent malignancies.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Uncovering a novel treatment strategy: sodium butyrate overcomes cisplatin resistance in the oral squamous cell carcinoma by inducing ferroptosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月16日

查看全文
  • Bing Wang,
  • Wei Li,
  • Yujia Bai,
  • Zhangci Su,
  • Qingwen Zeng,
  • Chao Lv,
  • Qinchao Hu,
  • Bin Cheng,
  • Xiaoan Tao

摘要

Background

Chemoresistance to platinum-based agents like cisplatin is a major therapeutic challenge in advanced oral squamous cell carcinoma (OSCC), with 70–80% of recurrent cases developing resistance that severely compromises clinical outcomes. The mechanism of cisplatin resistance still remains unclear and requires further investigation. This study investigated ferroptosis suppression as a mechanism underlying this resistance and explored the therapeutic potential of the histone deacetylase (HDAC) inhibitor sodium butyrate (NaB).

Methods

Cisplatin-resistant OSCC cells (CAL27/CDDP) and parental cells (CAL27) were used to assess ferroptosis levels and resistance mechanisms. The effects of NaB on reversing cisplatin resistance and inhibiting malignant behaviors (proliferation, migration, invasion) were evaluated in vitro. Mechanistic studies, including identification of key regulators and epigenetic modifications were conducted. The therapeutic effect was further validated in vivo using xenograft tumor models treated with NaB and cisplatin.

Results

CAL27/CDDP exhibited significant ferroptosis suppression compared to CAL27. NaB effectively reversed cisplatin resistance and inhibited malignant behaviors in both cell lines. Mechanistic exploration revealed that NaB enhanced acetylation at the promoter region of early growth response protein 1 (EGR1) through HDAC9 inhibition, elevating its transcriptional activity. EGR1 functioned as a transcription factor to upregulate cytochrome P450 oxidoreductase (POR) expression, potentiating ferroptosis execution. In vivo experiments further confirmed the therapeutic relevance of this HDAC9/EGR1/POR signaling pathway, as NaB administration significantly sensitized xenograft tumors to cisplatin treatment.

Conclusions

These findings position NaB as a promising epigenetic modulator for overcoming cisplatin resistance in OSCC models, with immediate clinical implications. The identified pathway offers a redox biology-based therapeutic strategy that could be extended to other chemotherapy-resistant solid tumors, potentially revolutionizing the treatment paradigm for recurrent malignancies.