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<p>Colorectal cancer (CRC) remains a major global health challenge, with steadily increasing incidence and mortality. Current diagnostic biomarkers exhibit limited clinical utility due to insufficient sensitivity and specificity. While cellular senescence promotes CRC development through chronic inflammation and senescence-associated secretory phenotype (SASP), and hypoxia paradoxically drives malignant progression in tumors despite suppressing growth in normal tissues, the underlying mechanisms connecting these pathways remain incompletely understood. This study reveals that heat shock protein 72 (HSP72) orchestrates CRC progression under hypoxic conditions through a hypoxia-inducible factor 1 α (HIF1α)–HSP72–AMPK positive feedback loop. Specifically, hypoxia stabilizes HIF1α, enabling its specific binding to the 1207&#xa0;bp region of the HSP72 promoter and subsequent transcriptional upregulation. Then, HSP72 regulates AMPK pathway activation, forming a signaling hub that maintains HIF1α stability and thereby couples metabolic reprogramming with sustained tumor proliferation. This circuit further enables senescence evasion by suppressing SA-β-Gal activity, blocking SASP factor secretion, and enhancing anti-apoptotic pathways. Clinical translation demonstrates that circulating HSP72 serves as both an early diagnostic biomarker and an independent predictor of metastatic risk. Collectively, our findings establish HSP72 with dual significance—as a promising molecular marker for non-invasive early detection and as a theoretical foundation for targeting the HSP72-AMPK pathway and disrupting the HIF1α–HSP72 axis, offering novel strategies against hypoxia-adapted and therapy-resistant CRC.</p> Graphical abstract <p></p>

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HSP72-AMPK axis mitigates hypoxia-induced cellular senescence to promote colorectal cancer development

  • 期刊论文

  • 发表日期：

    2026年1月2日

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  • Gege Liu,
  • Xuanlin Wang,
  • Xu Yang,
  • Junlu Wu,
  • Yaran Li,
  • Yao Lu,
  • Anquan Shang,
  • Chen Chen,
  • Ruixin Sun

摘要

Colorectal cancer (CRC) remains a major global health challenge, with steadily increasing incidence and mortality. Current diagnostic biomarkers exhibit limited clinical utility due to insufficient sensitivity and specificity. While cellular senescence promotes CRC development through chronic inflammation and senescence-associated secretory phenotype (SASP), and hypoxia paradoxically drives malignant progression in tumors despite suppressing growth in normal tissues, the underlying mechanisms connecting these pathways remain incompletely understood. This study reveals that heat shock protein 72 (HSP72) orchestrates CRC progression under hypoxic conditions through a hypoxia-inducible factor 1 α (HIF1α)–HSP72–AMPK positive feedback loop. Specifically, hypoxia stabilizes HIF1α, enabling its specific binding to the 1207 bp region of the HSP72 promoter and subsequent transcriptional upregulation. Then, HSP72 regulates AMPK pathway activation, forming a signaling hub that maintains HIF1α stability and thereby couples metabolic reprogramming with sustained tumor proliferation. This circuit further enables senescence evasion by suppressing SA-β-Gal activity, blocking SASP factor secretion, and enhancing anti-apoptotic pathways. Clinical translation demonstrates that circulating HSP72 serves as both an early diagnostic biomarker and an independent predictor of metastatic risk. Collectively, our findings establish HSP72 with dual significance—as a promising molecular marker for non-invasive early detection and as a theoretical foundation for targeting the HSP72-AMPK pathway and disrupting the HIF1α–HSP72 axis, offering novel strategies against hypoxia-adapted and therapy-resistant CRC.

Graphical abstract