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This study aimed to develop and evaluate ferulic acid-loaded chitosan nanoparticles (FA-ChNPs) as a multimodal radiosensitizer targeting STAT3, caspase-8, and p53 pathways in Ehrlich ascites carcinoma (EAC). FA-ChNPs were synthesized using ionic gelation and thoroughly characterized for their physicochemical properties, including size, and zeta potential through TEM and DLS. The encapsulation efficiency was verified using UV\u2013Vis spectroscopy. In vitro drug release kinetics were evaluated using the dialysis bag method, demonstrating a sustained release profile from the nanoparticles. Biological evaluation included acute toxicity testing in healthy mice to determine the LD50 value according to OECD guidelines. For antitumor assessment, EAC-bearing mice were divided into six treatment groups (n equals 6 per group), receiving either FA-ChNPs alone (115.75mg\/kg via oral gavage), gamma-irradiation alone (6Gy per week), or combination therapy. Comprehensive biological parameters were measured, including tumor progression (mass and volume), metabolic profile (total cholesterol, triglycerides, HDL-C), liver and kidney function markers (ALT, AST, ALP, creatinine, urea), oxidative stress indicators (GSH, SOD, CAT, MDA), inflammatory cytokines (TNF-alpha, IL-6, VEGF), and gene expression levels (STAT3, caspase 8, P53 via qRT-PCR). Histopathological examination of liver tissue complemented these analyses. In silico studies encompassed molecular docking with key targets (STAT3, caspase 8, TP53) and ADMET property predictions. The FA-ChNPs demonstrated favorable physicochemical properties, including a spherical morphology with an average particle size of 41.63 nm and good colloidal stability indicated by a PDI of 0.2, a zeta potential of -2.45 mV. Also, FA-ChNPs exhibited sustained in vitro drug release, contrasting with the rapid diffusion of free ferulic acid, which supports their potential for prolonged therapeutic action and a high safety margin with an LD\u2085\u2080 value of 2315mg\/kg. The combination therapy demonstrated superior antitumor effects, achieving 44.3% reduction in tumor mass and 67.0% reduction in tumor volume compared to EAC controls, with corresponding tumor dimensions reduced to 1.02cm (length)\u2009\u00d7\u20090.74cm (width), confirming potent radiosensitization and synergistic efficacy. Biological assessments revealed significant improvements across multiple parameters: metabolic profile showed 89.2% increase in HDL-C and 29.0% decrease in triglycerides; liver and kidney function markers improved with 29.0% reduction in ALT and 39.7% decrease in creatinine; oxidative stress modulation included 87.9% increase in GSH and 32.4% reduction in MDA; inflammatory markers decreased by 40% for TNF-alpha and 51.1% for IL-6. Molecular analyses showed 70% suppression of STAT3, 108.2% activation of caspase-8, and stabilization of p53. Histopathological evaluation confirmed preserved liver architecture with minimal steatosis and inflammation. Molecular docking studies revealed strong binding affinities:\u20146.02 kcal\/mol for STAT3, -7.31kcal\/mol for CASP8, and -5.15kcal\/mol for TP53. FA-ChNPs represent a groundbreaking approach to enhance radiotherapy efficacy through simultaneous pathway modulation and organoprotection. These findings support further clinical translation for treatment-resistant cancers.<\/jats:p>","DOI":"10.1038\/s41598-025-27352-8","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T12:20:18Z","timestamp":1764591618000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Ferulic acid-loaded chitosan nanoparticles enhance radiotherapy efficacy via STAT3 suppression and caspase-8\/p53 activation in Ehrlich ascites carcinoma"],"prefix":"10.1038","volume":"15","author":[{"given":"Mai Tamer","family":"Mansour","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed Abdalla","family":"Hussein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A.","family":"Emara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabab M.","family":"El-Sherif","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"issue":"3","key":"27352_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung, H. et al. 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All procedures followed the recommendations of the Ethics Committee to uphold the highest standards of animal care.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"No humans were used for studies that are the basis of this research. The reported experiments in accordance with the standards set forth in \"Guide for the Care and Use of Laboratory Animals.\" This study adheres to internationally accepted standards for animal research, following the 3Rs principle. The ARRIVE guidelines were employed for reporting experiments involving live animals, promoting ethical research practices.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human or animal rights"}}],"article-number":"42910"}}