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Background <p>Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target for colorectal cancer (CRC). However, the precise mechanisms by which CRC cells evade ferroptosis remain incompletely understood. Cysteine redox modification, typically catalyzed by cysteine oxidases, is a key regulatory factor governing protein structure and function. Quiescin sulfhydryl oxidase 1 (QSOX1), a Golgi-localized sulfhydryl oxidase known to promote various physiological functions, has an uncharacterized role in ferroptosis. Therefore, this study investigated the effects of QSOX1 on ferroptosis sensitivity in colorectal cancer.</p> Methods <p>We utilized a comprehensive set of analytical techniques to elucidate the mechanisms of QSOX1 in CRC ferroptosis resistance. We assessed cell proliferation, colony formation, and sensitivity to ferroptosis inducers (Erastin and RSL3) in CRC cells. Levels of reactive oxygen species (ROS), intracellular Fe<sup>2+</sup>, and redox metabolites were measured by biochemical assays and flow cytometry. RNA sequencing (RNA-seq) and untargeted metabolomics were performed using QSOX1-deficient HT-29 cells. The interaction between QSOX1 and SLC7A11 was confirmed via coimmunoprecipitation, immunofluorescence, and nonreducing gel electrophoresis. Cystine uptake and glutamate release assays were used to assess SLC7A11 function. Tumor xenografts were generated to assess the in vivo sensitivity of colon cancer cells to ferroptosis inducers.</p> Results <p>QSOX1 was significantly upregulated in CRC tissues and promoted CRC cell proliferation in vitro and in vivo. Knockdown of QSOX1 sensitized CRC cells to ferroptosis inducers, whereas QSOX1 overexpression conferred resistance. Mechanistically, QSOX1 enhanced redox homeostasis and GSH metabolism in CRC cells. QSOX1 interacted with and facilitated redox modification of SLC7A11 at cysteine 158 via its thioredoxin motif (C449-C452) in the ERV/ALR domain. This oxidative regulation enhanced SLC7A11 membrane localization, cystine uptake, and glutamate release, thereby boosting intracellular GSH synthesis and suppressing ferroptosis.</p> Conclusions <p>QSOX1 promotes ferroptosis resistance in CRC cells through redox-dependent post-translational modification of SLC7A11, enhancing its activity and promoting GSH synthesis. The QSOX1–SLC7A11 axis represents a potential therapeutic target to overcome ferroptosis resistance in CRC.</p>

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QSOX1 confers ferroptosis resistance via redox modification of SLC7A11 in colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月15日

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  • Mengqi Jia,
  • Hanxiang Chen,
  • Yulin Liu,
  • Jianzhuang Guo,
  • Xiaofei Wang,
  • Qiang Liu,
  • Zhiheng Liu,
  • Zhaoqing Meng,
  • Chunqing Wang,
  • Yunqiu Wang

摘要

Background

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target for colorectal cancer (CRC). However, the precise mechanisms by which CRC cells evade ferroptosis remain incompletely understood. Cysteine redox modification, typically catalyzed by cysteine oxidases, is a key regulatory factor governing protein structure and function. Quiescin sulfhydryl oxidase 1 (QSOX1), a Golgi-localized sulfhydryl oxidase known to promote various physiological functions, has an uncharacterized role in ferroptosis. Therefore, this study investigated the effects of QSOX1 on ferroptosis sensitivity in colorectal cancer.

Methods

We utilized a comprehensive set of analytical techniques to elucidate the mechanisms of QSOX1 in CRC ferroptosis resistance. We assessed cell proliferation, colony formation, and sensitivity to ferroptosis inducers (Erastin and RSL3) in CRC cells. Levels of reactive oxygen species (ROS), intracellular Fe2+, and redox metabolites were measured by biochemical assays and flow cytometry. RNA sequencing (RNA-seq) and untargeted metabolomics were performed using QSOX1-deficient HT-29 cells. The interaction between QSOX1 and SLC7A11 was confirmed via coimmunoprecipitation, immunofluorescence, and nonreducing gel electrophoresis. Cystine uptake and glutamate release assays were used to assess SLC7A11 function. Tumor xenografts were generated to assess the in vivo sensitivity of colon cancer cells to ferroptosis inducers.

Results

QSOX1 was significantly upregulated in CRC tissues and promoted CRC cell proliferation in vitro and in vivo. Knockdown of QSOX1 sensitized CRC cells to ferroptosis inducers, whereas QSOX1 overexpression conferred resistance. Mechanistically, QSOX1 enhanced redox homeostasis and GSH metabolism in CRC cells. QSOX1 interacted with and facilitated redox modification of SLC7A11 at cysteine 158 via its thioredoxin motif (C449-C452) in the ERV/ALR domain. This oxidative regulation enhanced SLC7A11 membrane localization, cystine uptake, and glutamate release, thereby boosting intracellular GSH synthesis and suppressing ferroptosis.

Conclusions

QSOX1 promotes ferroptosis resistance in CRC cells through redox-dependent post-translational modification of SLC7A11, enhancing its activity and promoting GSH synthesis. The QSOX1–SLC7A11 axis represents a potential therapeutic target to overcome ferroptosis resistance in CRC.