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Free Radical Biology and Medicine

Free Radical Biology and Medicine

IF: 7.1
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Epimedokoreanin B blocks autophagic flux to inhibit progression of triple negative breast cancer through targeting MCOLN1/TRPML1 channel

Published:20 August 2025 DOI: 10.1016/j.freeradbiomed.2025.08.041
Chenyang Zhao , Peng Zhang , Xiaojuan Yang , Miao Liu , Zhirong Guan , Bin Ma , Xiangguo Duan , Chunxia Su

Abstract

Triple-negative breast cancer (TNBC) remains a highly malignant subtype with limited therapeutic options. Here, Epimedokoreanin B (EKB), a flavonoid derived from Epimedium brevicornum, is identified as a potent inhibitor of TNBC progression. Mechanistically, EKB directly binds MCOLN1/TRPML1, thereby promoting lysosomal Ca2+ efflux and impairing lysosomal acidification. This disruption specifically blocks autophagosome-lysosome fusion, leading to autophagic flux inhibition and subsequent accumulation of intracellular oxidants, including hydrogen peroxide (H2O2), related peroxides, and mitochondrial superoxide (O2?-). Importantly, the resulting oxidative stress acts as a critical mediator, ultimately triggering apoptosis. The specificity of the EKB-MCOLN1/TRPML1 interaction was validated through molecular docking, Cellular Thermal Shift Assay (CETSA), and pharmacological MCOLN1/TRPML1inhibition. In TNBC mouse models, EKB treatment significantly suppressed primary tumor growth and, notably, reduced pulmonary metastasis. Additionally, no systemic toxicity was observed. Furthermore, EKB treatment reprogrammed the tumor immune microenvironment, evidenced by increased infiltration of CD8+T cells and M1 macrophages alongside reduced immunosuppressive subsets. Taken together, these results establish EKB as a promising therapeutic candidate that couples autophagy blockade with immune activation, and highlight oxidative stress as a significant contributing mechanism underlying its anticancer effects.

Substances (26)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Rapamycin 53123-88-9 C51H79NO13 1033 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1033 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1033 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1033 suppliers $9.00-$6160.00
BAPTA 85233-19-8 C22H24N2O10 216 suppliers $8.00-$3850.00
BAPTA 85233-19-8 C22H24N2O10 216 suppliers $8.00-$3850.00
BAPTA 85233-19-8 C22H24N2O10 216 suppliers $8.00-$3850.00
BAPTA 85233-19-8 C22H24N2O10 216 suppliers $8.00-$3850.00
TPEN 16858-02-9 C26H28N6 195 suppliers $9.00-$4200.00
TPEN 16858-02-9 C26H28N6 195 suppliers $9.00-$4200.00

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