{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:24:12Z","timestamp":1787027052695,"version":"build-2736575974"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T00:00:00Z","timestamp":1769385600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Given the lack of targeted therapies and frequent resistance to apoptosis-based treatments, triple-negative breast cancer (TNBC) remains a major clinical challenge. Exploring non-apoptotic cell death mechanisms may offer new therapeutic avenues to circumvent drug resistance in TNBC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The anticancer activity of a novel cyclometalated iridium (III) compound, CIr2, was evaluated using cytotoxicity, clonogenic, and migration assays in multiple breast cancer cell lines. Mechanistic investigations included analyses of mitochondrial dysfunction, reactive oxygen species (ROS) production, ATP depletion, endoplasmic reticulum (ER) stress, and MAPK signaling. Transcriptomic profiling (RNA-seq), ultrastructural and morphological analyses, as well as pharmacological inhibitor studies targeting distinct cell death pathways, were performed to elucidate the mode of cell death induced by CIr2. The\n                      <jats:italic>in vivo<\/jats:italic>\n                      antitumor efficacy and safety of CIr2 were further assessed using a TNBC xenograft mouse model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CIr2 selectively inhibited the proliferation and migration of TNBC cells while exerting minimal cytotoxic effects on normal breast epithelial cells. CIr2 preferentially accumulated in mitochondria, leading to mitochondrial membrane potential collapse, excessive ROS production, and profound ATP depletion. Transcriptomic profiling and morphological analyses revealed pronounced ER stress, MAPK pathway activation, and paraptosis-associated ultrastructural alterations, including mitochondrial swelling and extensive cytoplasmic vacuolization. Pharmacological inhibition of apoptosis, necroptosis, ferroptosis, autophagy, ER stress, or p38 MAPK signaling failed to rescue CIr2-induced cytotoxicity, whereas ROS scavenging effectively reversed these effects, confirming a mitochondrial dysfunction and ROS-driven paraptotic mode of cell death.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , CIr2 markedly suppressed TNBC xenograft tumor growth with minimal systemic toxicity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>CIr2 induces paraptosis through mitochondrial dysfunction and ER stress, offering a potential therapeutic strategy to overcome apoptosis resistance in TNBC. These findings provide a new mechanistic insight into iridium-based paraptosis induction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1739226","type":"journal-article","created":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T07:18:54Z","timestamp":1769411934000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["A cyclometalated iridium(III) complex induces paraptotic cell death via mitochondrial dysfunction and ER stress in triple-negative breast cancer cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Houmin","family":"Lin","sequence":"first","affiliation":[{"name":"Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The First Affiliated Hospital of Guilin Medical University","place":["Guilin, Guangxi, China"]},{"name":"Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, The First Affiliated Hospital of Guilin Medical University","place":["Guilin, Guangxi, China"]},{"name":"China-USA Lipids in Health and Disease Research Center, Guilin Medical University","place":["Guilin, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Wei","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The First Affiliated Hospital of Guilin Medical University","place":["Guilin, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenmin","family":"Yao","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The First Affiliated Hospital of Guilin Medical University","place":["Guilin, Guangxi, China"]},{"name":"Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, The First Affiliated Hospital of Guilin Medical University","place":["Guilin, Guangxi, China"]},{"name":"China-USA Lipids in Health and Disease Research Center, Guilin Medical University","place":["Guilin, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinqin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Thyroid and Breast Surgery, Nanxishan Hospital of Guangxi Zhuang Autonomous Region","place":["Guilin, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfei","family":"Jin","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, The First Affiliated Hospital of Guilin Medical University","place":["Guilin, Guangxi, China"]},{"name":"Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, The First Affiliated Hospital of Guilin Medical University","place":["Guilin, Guangxi, China"]},{"name":"China-USA Lipids in Health and Disease Research Center, Guilin Medical University","place":["Guilin, Guangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"10835","DOI":"10.1039\/d2dt01875f","article-title":"A chemical perspective on the clinical use of platinum-based anticancer drugs","volume":"51","author":"Alassadi","year":"2022","journal-title":"Dalton Trans."},{"key":"B2","doi-asserted-by":"publisher","first-page":"115459","DOI":"10.1016\/j.bcp.2023.115459","article-title":"Current therapeutic approaches and promising perspectives of using bioengineered peptides in fighting chemoresistance in triple-negative breast cancer","volume":"210","author":"Azari","year":"2023","journal-title":"Biochem. 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