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Acetylcholine (ACh) is cardioprotective by enhancing heart rate variability and reducing mitochondrial dysfunction and inflammation. Nonetheless, the protective role of ACh in countering DOX-induced cardiotoxicity (DIC) remains underexplored as current approaches to increasing ACh levels are invasive and unsafe for patients. In this study, we explore the protective effects of ACh against DIC through three distinct ACh administration strategies: (i) freely-suspended 100 <jats:italic>\u00b5<\/jats:italic>M ACh; (ii) ACh-producing cholinergic neurons (CNs); or (iii) ACh-loaded nanoparticles (ACh-NPs). These are tested in <jats:italic>in vitro<\/jats:italic> cardiac spheroids (CSs), which have previously been shown to approximate the complex DIC. We assess ACh\u2019s protective effects by measuring the toxicity ratio (cell death\/viability), contractile activity, gene expression changes via qPCR and nitric oxide (NO) signaling. Our findings show that ACh effectively attenuates DOX-induced cell death and contractile dysfunction. ACh also counteracts the DOX-induced downregulation of genes controlling myocardial fibrosis, endothelial and cardiomyocyte dysfunction, and autonomic dysregulation. ACh cardioprotection against DOX is dependent on NO signaling in endothelial cells but not in cardiac myocytes or fibroblasts. Altogether, this study shows for the first time that elevating ACh levels showed a promising therapeutic approach for preventing DIC.<\/jats:p>","DOI":"10.1088\/1758-5090\/adb7c2","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T23:02:54Z","timestamp":1739919774000},"page":"025023","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Acetylcholine-loaded nanoparticles protect against doxorubicin-induced toxicity in <i>in vitro<\/i> cardiac spheroids"],"prefix":"10.1088","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9414-3499","authenticated-orcid":false,"given":"Clara","family":"Liu Chung Ming","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Runali","family":"Patil","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0353-4935","authenticated-orcid":true,"given":"Ahmed","family":"Refaat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean","family":"Lal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaowei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3689-4275","authenticated-orcid":true,"given":"Carmine","family":"Gentile","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"266","published-online":{"date-parts":[[2025,3,7]]},"reference":[{"key":"bfadb7c2bib1","doi-asserted-by":"publisher","first-page":"214","DOI":"10.2174\/157340311799960645","article-title":"Anthracycline cardiotoxicity prevalence, pathogenesis and treatment","volume":"7","author":"Volkova","year":"2011","journal-title":"Curr. 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