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<p>Gastric cancer (GC) is a deadly disease with poor prognosis and few treatment options. Tropomyosin 4 (TPM4) is an actin-binding protein that stabilizes the cytoskeleton of cells and has an unclear role in GC. This study aimed to elucidate the role and underlying mechanisms of TPM4 in GC pathogenesis. The expression and diagnostic and prognostic value of TPM4 in GC were analyzed using bioinformatics. A nomogram based on TPM4 expression was created and validated with an external cohort. <i>TPM4</i>-knockdown GC cells and xenograft models in nude mice were used to study the function of TPM4 in vitro and in vivo. Proteomic and rescue experiments confirmed the regulatory effect of TPM4 on stearoyl-CoA desaturase 1 (SCD1) in GC. Immunohistochemistry verified the expression and correlation of the TPM4 and SCD1 proteins in GC tissues. Our study identified TPM4 as an oncogene in GC, suggesting its potential diagnostic and prognostic value. The TPM4-based nomogram showed potential prognostic value for clinical use. <i>TPM4</i> knockdown inhibited GC cell proliferation, induced ferroptosis, and slowed tumor growth in vivo, which is achieved by inhibiting SCD1 expression. Immunohistochemical analysis of GC tissues revealed elevated expression levels of both TPM4 and SCD1 proteins, with a positive correlation observed between their expression. TPM4 is a promising target for new diagnostic, prognostic, and therapeutic strategies for GC. Downregulation of TPM4 inhibits GC cell growth and induces ferroptosis by suppressing SCD1 expression.</p> Graphical abstract <p></p> <p>Our study shows that inhibiting TPM4 expression significantly hinders GC cell proliferation and triggers ferroptosis, with SCD1 likely acting as a downstream target. Inhibiting SCD1 enhances sensitivity to ferroptosis by altering the SFA/MUFA ratio and induces apoptosis by initiating ER stress and UPR activation. This study suggests that the downregulation of TPM4 can inhibit the proliferation of GC cells and induce ferroptosis and apoptosis by suppressing SCD1 expression.</p>

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TPM4 influences the initiation and progression of gastric cancer by modulating ferroptosis via SCD1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月11日

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  • Ling-Lin Zhao,
  • Yu-Jun Liu,
  • Qi-Jing Guo,
  • Nan Yan,
  • Jie Yang,
  • Jing-Qi Han,
  • Xiao-Hong Xie,
  • Yu-Shuang Luo

摘要

Gastric cancer (GC) is a deadly disease with poor prognosis and few treatment options. Tropomyosin 4 (TPM4) is an actin-binding protein that stabilizes the cytoskeleton of cells and has an unclear role in GC. This study aimed to elucidate the role and underlying mechanisms of TPM4 in GC pathogenesis. The expression and diagnostic and prognostic value of TPM4 in GC were analyzed using bioinformatics. A nomogram based on TPM4 expression was created and validated with an external cohort. TPM4-knockdown GC cells and xenograft models in nude mice were used to study the function of TPM4 in vitro and in vivo. Proteomic and rescue experiments confirmed the regulatory effect of TPM4 on stearoyl-CoA desaturase 1 (SCD1) in GC. Immunohistochemistry verified the expression and correlation of the TPM4 and SCD1 proteins in GC tissues. Our study identified TPM4 as an oncogene in GC, suggesting its potential diagnostic and prognostic value. The TPM4-based nomogram showed potential prognostic value for clinical use. TPM4 knockdown inhibited GC cell proliferation, induced ferroptosis, and slowed tumor growth in vivo, which is achieved by inhibiting SCD1 expression. Immunohistochemical analysis of GC tissues revealed elevated expression levels of both TPM4 and SCD1 proteins, with a positive correlation observed between their expression. TPM4 is a promising target for new diagnostic, prognostic, and therapeutic strategies for GC. Downregulation of TPM4 inhibits GC cell growth and induces ferroptosis by suppressing SCD1 expression.

Graphical abstract

Our study shows that inhibiting TPM4 expression significantly hinders GC cell proliferation and triggers ferroptosis, with SCD1 likely acting as a downstream target. Inhibiting SCD1 enhances sensitivity to ferroptosis by altering the SFA/MUFA ratio and induces apoptosis by initiating ER stress and UPR activation. This study suggests that the downregulation of TPM4 can inhibit the proliferation of GC cells and induce ferroptosis and apoptosis by suppressing SCD1 expression.