Journal of Translational Medicine
·
2026
·Vol. 24
·期 1
·893
·
IF 9.7
Hao Zhihua,Su Xin,Li Jiantao,Jin Jing,Li Zheng,Yan Zhiqiang,Jiao Wenpeng,Jiao Wenjing,Wang Yingying,Ji Chenguang,Wang Xuan,He Yutong
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 (DMF 37 ) > 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.
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Cell Death Discovery
·
2023
·Vol. 9
·期 1
·1-15
·
IF 7
Lu Yang-yang,Zhu Chun-yang,Ding Yi-xin,Wang Bing,Zhao Shu-fen,Lv Jing,Chen Shu-ming,Wang Sha-sha,Wang Yan,Wang Rui,Qiu Wen-sheng,Qi Wei-wei
Cepharanthine (CEP), a bioactive compound derived from Stephania Cephalantha Hayata , is cytotoxic to various malignancies. However, the underlying mechanism of gastric cancer is unknown. CEP inhibited the cellular activity of gastric cancer AGS, HGC27 and MFC cell lines in this study. CEP-induced apoptosis reduced Bcl-2 expression and increased cleaved caspase 3, cleaved caspase 9, Bax, and Bad expression. CEP caused a G2 cell cycle arrest and reduced cyclin D1 and cyclin-dependent kinases 2 (CDK2) expression. Meanwhile, it increased oxidative stress, decreased mitochondrial membrane potential, and enhanced reactive oxygen species (ROS) accumulation in gastric cancer cell lines. Mechanistically, CEP inhibited Kelch-like ECH-associated protein (Keap1) expression while activating NF-E2 related factor 2 (Nrf2) nuclear translocations, increasing transcription of Nrf2 target genes quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), and glutamate-cysteine ligase modifier subunit (GCLM). Furthermore, a combined analysis of targeted energy metabolism and RNA sequencing revealed that CEP could alter the levels of metabolic substances such as D (+) - Glucose, D-Fructose 6-phosphate, citric acid, succinic acid, and pyruvic acid, thereby altering energy metabolism in AGS cells. In addition, CEP significantly inhibited tumor growth in MFC BALB/c nude mice in vivo, consistent with the in vitro findings. Overall, CEP can induce oxidative stress by regulating Nrf2/Keap1 and alter energy metabolism, resulting in anti-gastric cancer effects. Our findings suggest a potential application of CEP in gastric cancer treatment.
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Frontiers in Pharmacology
·
2022
·
IF 5.988
Minjun Yao,Caihua Zhang,Lingzhi Ni,Xiaoxiao Ji,Jianqiao Hong,Yazhou Chen,Jie Wang,Congsun Li,Jiyan Lin,Tingting Lu,Yihao Sheng,Menghao Sun,Mingmin Shi,Chenhe Zhou,Xunzi Cai
Osteoarthritis is a worldwide joint disease caused by abnormal chondrocytic metabolism. However, traditional therapeutic methods aimed at anti-inflammation for early-stage disease are palliative. In the present study, we demonstrated that cepharanthine (CEP), extracted from the plant Stephania cepharantha , exerted protective medicinal efficacy on osteoarthritis for the first time. In our in vitro study, CEP suppressed the elevated expression of matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and inducible nitric oxide synthase (iNOS) stimulated by IL-1β or TNF-α by inhibiting the activation of MAPK and NF-κB signaling pathways, and upregulated the protein expression of aggrecan, collagen II, and Sox9. Also, CEP could reverse the reduced level of cellular autophagy in IL-1β or TNF-α–induced chondrocytes, indicating that the protective effect of CEP on osteoarthritis was achieved by restoring MAPK/NF-κB-mediated autophagy. Furthermore, in a murine OA model, CEP mitigated cartilage degradation and prevented osteoarthritis in the CEP-treated groups versus the OA group. Hence, our results revealed the therapeutic prospect of CEP for anti-osteoarthritic treatment.
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Life-Basel
·
2026
·Vol. 16
·期 9
·1560
·
IF 3.9
Tongshan Zhu,Shumei Zhang,Mengxin Hao,Ling Wan,Fulei Nie,Guowei Zhang,Bingrui Liu,Chunyu Tian,Xinyue Wang,Haibin Liu,Yijia Li,Yuhan Feng,Di Guo,Nan Li,Yingchao Zhang,Pengcai Liu,Fan Shi,Shuoqian Ma,Rui Cao,Liangdan Sun,Xiaoming Song
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, and gemcitabine (GEM) resistance is a major contributor to its poor clinical outcomes, generating an urgent need for novel therapeutic strategies targeting tumor proliferation and tumor-cell-intrinsic malignant signaling. This study aimed to investigate the synergistic anti-PDAC efficacy and underlying mechanism of cepharanthine (CEP) combined with GEM. A series of in vitro and in vivo experiments were performed to evaluate the antitumor activity, synergistic effect and preliminary in vivo safety of the CEP-GEM combination. Bioinformatics analysis coupled with experimental validation was applied to dissect the underlying mechanisms. The results demonstrated that CEP produced marked synergistic effects with GEM to suppress PDAC growth both in vitro and in vivo. Mechanistic investigations revealed that CEP blocked the PI3K/AKT/mTOR pathway and reduced tumor-cell-intrinsic PD-1/PD-L1 levels, thereby facilitating tumor-cell apoptosis, restraining cell migration and invasion, and sensitizing GEM-relatively insensitive AsPC-1 cells to GEM. Under our experimental conditions, no obvious histopathological injury or prominent systemic toxicity was observed. In conclusion, this work provides preclinical evidence showing that the CEP-GEM combination exerts anti-tumor activity via dual-pathway suppression in PDAC cells, and supports further translational research for PDAC.
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SEPARATION AND PURIFICATION TECHNOLOGY
·
2025
·
IF 9
Min-Hui Zhang,Shu-Yu Bao,Ke Zheng,Hai-Li Sun,Ye-Jia Li,Xi-Can Li,Quan-Zhou Wu,Jian-Feng He
The high specificity of molecularly imprinted polymers (MIPs) in recognition is pivotal for their practical application. In this study, highly specific molecularly imprinted microspheres were prepared for cepharanthine (CEP) using a shielding strategy to mitigate non-selective adsorption sites within MIPs. Carboxyl-functionalized microspheres (CPMs) were initially fabricated as the support by copolymerizing octavinyl polyhedral oligomeric silsesquioxanes (OV-POSS), methacrylic acid (MAA), and methyl methacrylate (MMA) through suspension polymerization. Cepharanthine, serving as the template molecule,was adsorbed onto the CPMs via hydrogen bonding and electrostatic interactions. Subsequently, a thin imprinted layer was deposited onto the microspheres through cross-linking polymerization of MAA and ethylene glycol dimethacrylate (EDMA). The excessive carboxyl groups within the polymer matrix were shielded by forming an alkaline coating film via the oxidative self-polymerization reaction of dopamine (DA) and polyethyleneimine (PEI). After the removal of the CEP template, the shielded molecularly imprinted microspheres (SMIMs) exhibited a significantly higher adsorption capacity for CEP (330.42μmol g −1 ) compared to the corresponding non-imprinted microspheres, which had an adsorption capacity of only 2.93μmol g −1 . Selectivity studies demonstrated that the SMIMs exhibited superior recognition specificity for CEP and its structural analogs, with an imprinting factor of up to 133.06. Furthermore, the SMIMs were employed in solid-phase extraction for the specific separation of CEP directly from Stephania epigaea Lo extracts. The elution recoveries of CEP were in range of 98.3 %−103.5 % with relative standard deviation (RSD) of below 1.9 % (n = 3).
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