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Background <p>Characterized by irreversible weight loss and frailty, cancer cachexia affects 50–80% of those with advanced cancer, causing progressive functional decline and contributing to roughly 20% of cancer deaths. Findings from recent research suggest that muscle wasting due to cachexia is a significant cause of death in cancer patients. In the context of colorectal cancer, FOXS1 promotes tumor progression by upregulating CXCL8. Its role in cancer cachexia, however, has not been investigated.</p> Objective <p>This investigation sought to determine the mechanism of FOXS1 in cancer cachexia-induced muscle atrophy.</p> Results <p>FOXS1 was up-regulated in C2C12 myotubes treated with CT26 cell conditioned medium, and inhibiting FOXS1 lowered Atrogin1 and MuRF1 protein expression and ameliorated atrophy of myotubes. FOXS1 modulated PIK3IP1 protein stability through PIK3IP1 ubiquitination. Downregulating PIK3IP1 attenuated the inhibitory effect of inhibiting FOXS1 on Atrogin1 and MuRF1 protein expression and its ameliorative effect on myotube atrophy. Inhibiting FOXS1 increased tumor-free body weight, GA weight, and GA myofiber cross-sectional area in mice. FOXS1 activated the PI3K/AKT signaling through downregulating PIK3IP1.</p> Conclusion <p>FOXS1 promotes cancer cachexia-induced muscle atrophy by down-regulating PIK3IP1 to activate the PI3K/AKT signaling.</p>

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FOXS1 promotes cancer cachexia-induced muscle atrophy by down-regulating PIK3IP1 to activate the PI3K/AKT signaling

  • 期刊论文

  • 发表日期：

    2025年11月6日

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  • AnLong Yao,
  • GuangKe Li,
  • XuDong Gu,
  • LiLi Cao,
  • Peng Zheng

摘要

Background

Characterized by irreversible weight loss and frailty, cancer cachexia affects 50–80% of those with advanced cancer, causing progressive functional decline and contributing to roughly 20% of cancer deaths. Findings from recent research suggest that muscle wasting due to cachexia is a significant cause of death in cancer patients. In the context of colorectal cancer, FOXS1 promotes tumor progression by upregulating CXCL8. Its role in cancer cachexia, however, has not been investigated.

Objective

This investigation sought to determine the mechanism of FOXS1 in cancer cachexia-induced muscle atrophy.

Results

FOXS1 was up-regulated in C2C12 myotubes treated with CT26 cell conditioned medium, and inhibiting FOXS1 lowered Atrogin1 and MuRF1 protein expression and ameliorated atrophy of myotubes. FOXS1 modulated PIK3IP1 protein stability through PIK3IP1 ubiquitination. Downregulating PIK3IP1 attenuated the inhibitory effect of inhibiting FOXS1 on Atrogin1 and MuRF1 protein expression and its ameliorative effect on myotube atrophy. Inhibiting FOXS1 increased tumor-free body weight, GA weight, and GA myofiber cross-sectional area in mice. FOXS1 activated the PI3K/AKT signaling through downregulating PIK3IP1.

Conclusion

FOXS1 promotes cancer cachexia-induced muscle atrophy by down-regulating PIK3IP1 to activate the PI3K/AKT signaling.