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Background <p>Therapeutic resistance in colorectal cancer (CRC) is frequently linked to dysregulated protein homeostasis, which enables tumor cells to evade cell death. The ubiquitin-proteasome system (UPS) plays a pivotal role in regulating protein stability and has been implicated in ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation. Otubain1 (OTUB1), a deubiquitinase within the UPS, is hypothesized to regulate ferroptosis by stabilizing GPX4, a key inhibitor of ferroptosis.</p> Aim <p>This study investigates the regulatory role of OTUB1 in ferroptosis through its interaction with GPX4, aiming to uncover a novel therapeutic axis for CRC.</p> Methods <p>OTUB1 expression was manipulated in CRC cells using siRNA-mediated knockdown and plasmid-based overexpression. GPX4 expression, ROS levels, lipid peroxidation, and cell viability were assessed using qRT-PCR, Western blotting, and functional assays. Co-immunoprecipitation (Co-IP) assay was performed to confirm the interaction between OTUB1 and GPX4.</p> Results <p>OTUB1 knockdown led to a significant reduction in GPX4 protein levels, leading to elevated ROS, increased lipid peroxidation, and decreased cell viability. Conversely, GPX4 overexpression in OTUB1-knockdown cells restored cell viability and reversed ferroptosis markers (<i>P</i> &lt; 0.01). Co-IP assay confirmed that OTUB1 interacted with GPX4 and prevented its ubiquitin-mediated degradation, thereby stabilizing GPX4.</p> Conclusion <p>This study identifies OTUB1 as a novel regulator of ferroptosis in CRC through the stabilization of GPX4. Targeting the OTUB1-GPX4 axis may provide a new therapeutic approach for inducing ferroptosis in CRC cells, potentially overcoming resistance to conventional therapies and improving patient outcomes.</p>

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OTUB1 promotes colorectal cancer progression by stabilizing GPX4 and inhibiting ferroptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • Guofeng Lin,
  • Xi Lin,
  • Qihuang Lin,
  • Jianfeng Zhao

摘要

Background

Therapeutic resistance in colorectal cancer (CRC) is frequently linked to dysregulated protein homeostasis, which enables tumor cells to evade cell death. The ubiquitin-proteasome system (UPS) plays a pivotal role in regulating protein stability and has been implicated in ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation. Otubain1 (OTUB1), a deubiquitinase within the UPS, is hypothesized to regulate ferroptosis by stabilizing GPX4, a key inhibitor of ferroptosis.

Aim

This study investigates the regulatory role of OTUB1 in ferroptosis through its interaction with GPX4, aiming to uncover a novel therapeutic axis for CRC.

Methods

OTUB1 expression was manipulated in CRC cells using siRNA-mediated knockdown and plasmid-based overexpression. GPX4 expression, ROS levels, lipid peroxidation, and cell viability were assessed using qRT-PCR, Western blotting, and functional assays. Co-immunoprecipitation (Co-IP) assay was performed to confirm the interaction between OTUB1 and GPX4.

Results

OTUB1 knockdown led to a significant reduction in GPX4 protein levels, leading to elevated ROS, increased lipid peroxidation, and decreased cell viability. Conversely, GPX4 overexpression in OTUB1-knockdown cells restored cell viability and reversed ferroptosis markers (P < 0.01). Co-IP assay confirmed that OTUB1 interacted with GPX4 and prevented its ubiquitin-mediated degradation, thereby stabilizing GPX4.

Conclusion

This study identifies OTUB1 as a novel regulator of ferroptosis in CRC through the stabilization of GPX4. Targeting the OTUB1-GPX4 axis may provide a new therapeutic approach for inducing ferroptosis in CRC cells, potentially overcoming resistance to conventional therapies and improving patient outcomes.