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Background <p>Metabolic reprogramming underpins the acquisition of radioresistance in esophageal squamous cell carcinoma (ESCC); however, the specific bioenergetic vulnerabilities and direct pharmacological targets remain to be fully elucidated. This study defines a distinct metabolic phenotype conferring radioresistance and evaluates the natural alkaloid Cepharanthine (CEP) as a mechanism-driven radiosensitizer. </p> Methods <p>Matched clinical cohorts of radiosensitive and radioresistant ESCC patients were analyzed using widely-targeted and targeted metabolomics. Bioenergetic profiling (ECAR/OCR) was performed on established isogenic radioresistant cells. The mechanistic interactions between CEP and its target were mapped via network pharmacology, surface plasmon resonance (SPR), cellular thermal shift assays (CETSA), ubiquitin-proteasomal degradation assays, and Q347A site-directed mutagenesis. In vivo efficacy was validated across human cell-derived xenografts (CDX) and immunocompetent syngeneic (AKR/C57BL/6) mouse models. </p> Results <p>Clinical multi-omics revealed a "metabolic duality" in radioresistant ESCC, characterized by the concurrent hyperactivation of glycolysis and oxidative phosphorylation (OXPHOS). CEP administration disrupted this metabolic network, significantly sensitizing ESCC cells to irradiation [Dose-modifying factor at 37% survival (DMF<sub>37</sub>) &gt; 1]. Mechanistically, CEP directly engages the kinase domain of p70S6K—a structural interaction dependent on the Q347 residue—and triggers its ubiquitin-proteasomal degradation. This targeted clearance disrupts the upstream PI3K/Akt/mTOR survival axis. Genetic overexpression of wild-type p70S6K, but not the Q347A mutant, rescued the dual hypermetabolic phenotype and reinstated radioresistance. Clinically, elevated p70S6K expression correlated with poor disease-free survival and therapeutic failure. In vivo, CEP synergized with radiotherapy to suppress tumor kinetics in both CDX and syngeneic models, while concurrently enhancing CD8<sup>+</sup> T cell infiltration in the immunocompetent microenvironment, with no observable systemic toxicity. </p> Conclusions <p>Radioresistant ESCC relies on a dual hypermetabolic state driven by the PI3K/Akt/mTOR/p70S6K cascade. CEP overcomes this radioresistance by physically binding to and degrading p70S6K, thereby inducing bioenergetic exhaustion and reshaping the anti-tumor microenvironment. These findings provide a solid mechanistic rationale for translating CEP into clinical radiotherapeutic regimens.</p>

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Repurposing cepharanthine as a radiosensitizer in esophageal squamous cell carcinoma through dual metabolic intervention and direct targeting of p70s6K

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月3日

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  • Zhihua Hao,
  • Xin Su,
  • Jiantao Li,
  • Jing Jin,
  • Zheng Li,
  • Zhiqiang Yan,
  • Wenpeng Jiao,
  • Wenjing Jiao,
  • Yingying Wang,
  • Chenguang Ji,
  • Xuan Wang,
  • Yutong He

摘要

Background

Metabolic reprogramming underpins the acquisition of radioresistance in esophageal squamous cell carcinoma (ESCC); however, the specific bioenergetic vulnerabilities and direct pharmacological targets remain to be fully elucidated. This study defines a distinct metabolic phenotype conferring radioresistance and evaluates the natural alkaloid Cepharanthine (CEP) as a mechanism-driven radiosensitizer.

Methods

Matched clinical cohorts of radiosensitive and radioresistant ESCC patients were analyzed using widely-targeted and targeted metabolomics. Bioenergetic profiling (ECAR/OCR) was performed on established isogenic radioresistant cells. The mechanistic interactions between CEP and its target were mapped via network pharmacology, surface plasmon resonance (SPR), cellular thermal shift assays (CETSA), ubiquitin-proteasomal degradation assays, and Q347A site-directed mutagenesis. In vivo efficacy was validated across human cell-derived xenografts (CDX) and immunocompetent syngeneic (AKR/C57BL/6) mouse models.

Results

Clinical multi-omics revealed a "metabolic duality" in radioresistant ESCC, characterized by the concurrent hyperactivation of glycolysis and oxidative phosphorylation (OXPHOS). CEP administration disrupted this metabolic network, significantly sensitizing ESCC cells to irradiation [Dose-modifying factor at 37% survival (DMF37) > 1]. Mechanistically, CEP directly engages the kinase domain of p70S6K—a structural interaction dependent on the Q347 residue—and triggers its ubiquitin-proteasomal degradation. This targeted clearance disrupts the upstream PI3K/Akt/mTOR survival axis. Genetic overexpression of wild-type p70S6K, but not the Q347A mutant, rescued the dual hypermetabolic phenotype and reinstated radioresistance. Clinically, elevated p70S6K expression correlated with poor disease-free survival and therapeutic failure. In vivo, CEP synergized with radiotherapy to suppress tumor kinetics in both CDX and syngeneic models, while concurrently enhancing CD8+ T cell infiltration in the immunocompetent microenvironment, with no observable systemic toxicity.

Conclusions

Radioresistant ESCC relies on a dual hypermetabolic state driven by the PI3K/Akt/mTOR/p70S6K cascade. CEP overcomes this radioresistance by physically binding to and degrading p70S6K, thereby inducing bioenergetic exhaustion and reshaping the anti-tumor microenvironment. These findings provide a solid mechanistic rationale for translating CEP into clinical radiotherapeutic regimens.