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Ferroptosis-related oxaliplatin resistance in multiple cancers: Potential roles and therapeutic Implications
Sijia Zhong1, Zihan Wang2, Jiaxi Yang1
1Department of Gastrointestinal Surgery, the First Hospital of China Medical University, Shenyang, 110001, Liaoning Province, China.
Abstract:
Oxaliplatin (OXA)-based therapy is effective in the treatment of multiple cancers. However, primary or acquired OXA resistance remains an emerging challenge for its clinical application. Ferroptosis is an iron-dependent mode of cell death that has been demonstrated to play an essential role in the chemoresistance of many drugs, including OXA. In particular, dysregulation of SLC7A11-GPX4, one of the major antioxidant systems of ferroptosis, was found in the OXA resistance of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). In addition, Nrf2, the upstream regulator of GPX4 and many other antioxidant factors, is also involved in the OXA resistance of CRC and HCC. Inhibition of SLC7A11-GPX4 or Nrf2 by genetic deletion of pharmaceutical inhibition could significantly reverse OXA resistance. Long noncoding RNA (lncRNA) also participates in chemoresistance and ferroptosis of cancer cells. Specifically, LINC01134 promotes the recruitment of Nrf2 to the promoter of GPX4, thereby exerting transcriptional regulation of GPX4, which eventually increases the OXA sensitivity of HCC through upregulation of ferroptosis. On the other hand, a novel lncRNA DACT3-AS1 sensitizes gastric cancer cells to OXA through miR-181a-5p/sirtuin 1(SIRT1)-mediated ferroptosis. Therapies based on ferroptosis or a combination of OXA and ferroptosis enhancers could provide new therapeutic insights to overcome OXA resistance. In the present review, we present the current understanding of ferroptosis-related OXA resistance, highlight ferroptosis pathogenesis in OXA chemoresistance, and summarize available therapies that target OXA resistance by enhancing ferroptosis.
Insights
Oxaliplatin resistance in cancers can be overcome by targeting ferroptosis, a cell death pathway. Enhancing ferroptosis or combining it with Oxaliplatin shows promise for improved cancer treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Oxaliplatin (OXA) is a key chemotherapy drug, but resistance is a major clinical hurdle.
- Ferroptosis, an iron-dependent cell death, is implicated in OXA resistance, particularly via the SLC7A11-GPX4 axis and Nrf2 regulation.
- Long noncoding RNAs (lncRNAs) like LINC01134 and DACT3-AS1 modulate ferroptosis and OXA sensitivity in various cancers.
Purpose of the Study:
- To review the role of ferroptosis in Oxaliplatin resistance.
- To highlight the molecular mechanisms linking ferroptosis pathways (SLC7A11-GPX4, Nrf2, lncRNAs) to OXA resistance in cancers like CRC, HCC, and gastric cancer.
- To summarize therapeutic strategies targeting ferroptosis to overcome OXA resistance.
Main Methods:
- Literature review of studies on Oxaliplatin resistance, ferroptosis, and cancer.
- Analysis of molecular pathways involved in ferroptosis regulation, including SLC7A11-GPX4, Nrf2, and specific lncRNAs (LINC01134, DACT3-AS1).
- Examination of therapeutic interventions targeting ferroptosis to reverse chemoresistance.
Main Results:
- Dysregulation of the SLC7A11-GPX4 system and Nrf2 is a common mechanism in OXA resistance.
- Specific lncRNAs, LINC01134 and DACT3-AS1, were identified as regulators of ferroptosis, influencing OXA sensitivity in HCC and gastric cancer, respectively.
- Genetic or pharmaceutical inhibition of ferroptosis pathways can reverse OXA resistance.
Conclusions:
- Ferroptosis plays a critical role in Oxaliplatin resistance across multiple cancer types.
- Targeting ferroptosis, through inhibition of key regulators or combination therapies with OXA, offers a promising strategy to overcome chemoresistance.
- Further research into ferroptosis-based therapies could lead to novel treatment approaches for OXA-resistant cancers.
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