Precision tumor targeting: gamma-irradiated ellagic acid therapy for ferroptosis and necroptosis modulation via GPX4/ALOX/RIPK/MLKL pathway inhibition.

Alaa Elmetwalli, Roaa Alaa, Amany I Youssef, Tarek El-Sewedy, Ahmed M Eldrieny, Neveen A Hussein, Mohammed Salama, Ahmed E Noreldin, Jihan Hassan

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Article in Naunyn-Schmiedeberg's archives of pharmacology, 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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5 · Who and what money

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9 authors.

Alaa ElmetwalliPrince Fahad bin Sultan Research Chair for Biomedical Research, University of Tabuk, Tabuk, Saudi Arabia. aelmetwalli@ut.edu.sa.ORCID http://orcid.org/0000-0001-5372-4297

Roaa AlaaMaster's Student of the Department of Applied Medical Chemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt.

Amany I YoussefDepartment of Applied Medical Chemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt.

Tarek El-SewedyDepartment of Applied Medical Chemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt.

Ahmed M EldrienyFaculty of Applied Health Sciences Technology, Pharos University, Alexandria, 21526, Egypt.

Neveen A HusseinDepartment of Applied Medical Chemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt.

Mohammed SalamaDepartment of Histochemistry and Cell Biology, Medical Research Institute, Alexandria University, Alexandria, Egypt.

Ahmed E NoreldinDepartment of Histology and Cytology, Faculty of Veterinary Medicine, Damanhour University, Damanhour , 22511, Egypt.

Jihan HassanDepartment of Applied Medical Chemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Ellagic acid (EA) is a natural polyphenol with anticancer potential but limited efficacy due to stability and bioavailability constraints. Gamma irradiation has been proposed as a strategy to enhance its activity, yet its structural consequences and biological relevance remain underexplored. EA and irradiated EA (IEA) were systematically compared through structural and physicochemical characterization (FTIR, SEM, TEM, zeta potential, XRD, GC-MS with NIST library matching) and biological evaluation in Ehrlich ascites carcinoma (EAC)-bearing mice. FTIR, SEM/TEM, and zeta analysis indicated irradiation-induced surface and functional group modifications, while XRD confirmed preserved crystallinity with modest reductions in crystallite size. GC-MS annotation revealed multiple derivatized EA/IEA peaks with NIST match scores > 90%, suggesting subtle alterations in fragmentation patterns rather than formation of new compounds. Biologically, IEA demonstrated significantly greater tumor growth inhibition compared with EA and enhanced survival. Gene expression analyses revealed marked downregulation of necroptotic mediators (HSP90α, MLKL, RIPK1) and upregulation of ferroptosis-protective GPX4 (fold change 3.78 ± 0.61 in IEA + DOX), with synergistic effects observed in combination therapy. Gamma irradiation induces measurable physicochemical modifications in EA that underpin enhanced anticancer activity. These findings highlight IEA as a promising therapeutic candidate and illustrate the utility of irradiation for modulating polyphenolic compounds in cancer therapy.

Indexed as

Antineoplastic AgentsCarcinoma, Ehrlich TumorEllagic AcidFerroptosisAnimalsCell Line, TumorFemaleGamma RaysMaleMiceNecroptosisPhospholipid Hydroperoxide Glutathione PeroxidaseProtein KinasesSignal TransductionAntineoplastic AgentsEllagic AcidPhospholipid Hydroperoxide Glutathione PeroxidaseProtein KinasesDoxorubicin (DOX)Ellagic acid (EA)FerroptosisGamma irradiationGene expressionNecroptosis

Identifiers

PMID41168436

DOI10.2174/0109298673284605240301035057

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