{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:09:59Z","timestamp":1790096999605,"version":"4.0.1"},"reference-count":53,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Capsaicin, the principal bioactive compound of chilli peppers, has emerged as a promising natural molecule with anticancer potential in several malignancies, including colorectal cancer. However, the molecular mechanisms underlying its effects in colorectal cancer cells remain incompletely understood. In the present study, we investigated the effects of capsaicin on Caco-2 human colorectal adenocarcinoma cells, focusing on cell viability, proliferation, migration, cell-cycle regulation, and autophagy. Capsaicin (50\u2013200 \u00b5M) reduced cell viability in a dose- and time-dependent manner and significantly inhibited proliferation and migratory capacity. Capsaicin induced G2\/M cell-cycle arrest, accompanied by increased p21 expression and reduced p53 phosphorylation. Notably, capsaicin-induced cytotoxicity was not associated with activation of caspase-dependent apoptosis and was instead associated with marked accumulation of autophagic structures and increased LC3B-II\/LAMP-1 co-localization. Chloroquine co-treatment failed to further increase LC3B-II or p62 accumulation, indicating that autophagic degradation was already impaired. Although lysosomal abundance remained unchanged, capsaicin significantly reduced mature cathepsin-D protein, demonstrating compromised lysosomal degradative capacity and defective autophagic flux. In addition, capsaicin upregulated occludin expression, suggesting enhanced tight-junction integrity and reduced migratory potential. Collectively, these findings, at least explorative, demonstrate that capsaicin reduces Caco-2 cell viability and induces G2\/M cell-cycle arrest, accompanied by p21 upregulation and impaired lysosomal degradative capacity, highlighting disruption of the autophagy\u2013lysosomal pathway as a potential mechanism underlying its anticancer activity in Caco-2 cells.<\/jats:p>","DOI":"10.3390\/ijms27198435","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:32:12Z","timestamp":1790083932000},"page":"8435","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Capsaicin Induces G2\/M Cell-Cycle Arrest and Impairs Autophagy in Caco-2 Cells: An Exploratory Study"],"prefix":"10.3390","volume":"27","author":[{"given":"Hla","family":"Sudan","sequence":"first","affiliation":[{"name":"Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8345-9452","authenticated-orcid":false,"given":"Sofia","family":"Passaponti","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Roberta","family":"Romagnoli","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Laura","family":"Cresti","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4928-4652","authenticated-orcid":false,"given":"Mariangela","family":"Gentile","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4452-8128","authenticated-orcid":false,"given":"Maria","family":"Frosini","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9136-9983","authenticated-orcid":false,"given":"Anna Maria","family":"Aloisi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1080\/15548627.2017.1378838","article-title":"Autophagy Pathway: Cellular and Molecular Mechanisms","volume":"14","author":"Yu","year":"2018","journal-title":"Autophagy"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3425","DOI":"10.1002\/cbic.202100296","article-title":"An Autophagy-Disrupting Small Molecule Promotes Cancer Cell Death via Caspase Activation","volume":"22","author":"Park","year":"2021","journal-title":"ChemBioChem"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Tonkin-Reeves, A., Giuliani, C.M., and Price, J.T. 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