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

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.