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

Abstract 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.