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Increasingly it is being realized that TNBC does not respond well to current targeted therapies. This study aims to explore the antiproliferative effects and cancer regulatory mechanisms which underlie the drug resistance and aggressiveness of TNBC cells. Cryptocaryone (CPC) derived from\n                    <jats:italic>Cryptocarya concinna<\/jats:italic>\n                    demonstrated antiproliferative responses to TNBC cells (HCC1937 and MDA\u2010MB\u2010231), while normal breast cells (H184B5F5\/M10) exhibited low cytotoxicity. In an in vivo assessment, CPC effectively reduced tumor growth in the MDA\u2010MB\u2010231 xenografted mouse model without significantly affecting body weight. Mechanistically, CPC triggered apoptosis, as indicated by an increase in sub\u2010G1 and annexin V, as well as activated caspase 3 and 8. CPC also induced substantial oxidative stress by generating reactive oxygen species, mitochondrial superoxide, and membrane depolarization. CPC also induced oxidative DNA damage, as evidenced by the presence of \u03b3H2AX and 8\u2010hydroxy\u20102\u2010deoxyguanosine, in TNBC cells. All these CPC\u2010induced changes were more pronounced in TNBC cells than normal cells. JNK and p38 MAPK inhibitors attenuate CPC\u2010induced antiproliferation in TNBC cells. CPC upregulates phosphorylated JNK and p38 in TNBC cells.\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetylcysteine pretreatment confirmed that oxidative stress plays a vital role in enhancing the antiproliferation, apoptosis, and DNA damage in TNBC cells. Moreover, the CPC\u2010upregulated apoptosis and caspase 3\/8 activations in TNBC cells were inhibited by JNK and p38 inhibitors. The impact of ERK activation on antiproliferation and apoptosis was evident in MDA\u2010MB\u2010231 cells, but not in HCC1937 cells. In conclusion, CPC demonstrated antiproliferative effects on TNBC cells through apoptosis and DNA damage induced by oxidative stress and MAPK activation, while showing drug safety in normal cells and breast cancer mouse model.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70286","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T05:55:11Z","timestamp":1776664511000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cryptocaryone Exhibits ROS\/MAPK\u2010Dependent Antiproliferative and Apoptosis\u2010Inducing Effects on Triple\u2010Negative Breast Cancer Cells and Proof\u2010of\u2010Concept Breast Cancer Mouse Model"],"prefix":"10.1002","volume":"87","author":[{"given":"Ya\u2010Ting","family":"Chuang","sequence":"first","affiliation":[{"name":"Department of Biomedical Science and Environmental Biology PhD Program in Life Sciences, College of Life Science Kaohsiung Medical 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