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We have previously reported that CVB3 induces mitochondrial fission and mitophagy while inhibiting lysosomal degradation by blocking autophagosome-lysosome fusion. This promotes the release of virus-laden mitophagosomes from host cells as infectious extracellular vesicles (EVs), enabling non-lytic viral egress. Transient receptor potential vanilloid 1 (TRPV1), a heat and capsaicin-sensitive cation channel, regulates mitochondrial dynamics by inducing mitochondrial membrane depolarization and fission. In this study, we found that TRPV1 activation by capsaicin dramatically enhances CVB3 egress from host cells via EVs. Released EVs revealed increased levels of viral capsid protein VP1, mitochondrial protein TOM70, and fission protein phospho-DRP1. Moreover, these EVs were enriched in heat shock protein HSP70, suggesting its role in facilitating infectious EV release from cells. Furthermore, TRPV1 inhibition with capsazepine and SB-366791 significantly reduced viral infection in vitro. Our in vivo studies also found that SB-366791 significantly mitigates pancreatic damage and reduces viral titers in a mouse model of CVB3 pancreatitis. Given the lack of understanding regarding factors that contribute to diverse clinical manifestations of CVB3, our study highlights capsaicin and TRPV1 as potential exacerbating factors that facilitate CVB3 dissemination via mitophagy-derived EVs.<\/jats:p>","DOI":"10.3390\/ijms27020661","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T09:25:02Z","timestamp":1767950702000},"page":"661","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigating the Potential Role of Capsaicin in Facilitating the Spread of Coxsackievirus B3 via Extracellular Vesicles"],"prefix":"10.3390","volume":"27","author":[{"given":"Shruti","family":"Chatterjee","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, University of Alabama, Tuscaloosa, AL 35401, USA"},{"name":"Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, 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