ArticleJournal of translational medicine2026
Repurposing cepharanthine as a radiosensitizer in esophageal squamous cell carcinoma through dual metabolic intervention and direct targeting of p70s6K.
Article in Journal of translational medicine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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12 authors.
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Abstract
backgroundMetabolic 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.
methodsMatched 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.
resultsClinical 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
conclusionsRadioresistant 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.
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