{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:32Z","timestamp":1792790372251,"version":"4.5.0"},"posted":{"date-parts":[[2026,10,4]]},"group-title":"Cancer Biology","reference-count":44,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"name":"Scientific Research Innovation Program of the Shanghai Municipal Education Commission","award":["2023FGS2"],"award-info":[{"award-number":["2023FGS2"]}],"id":[{"id":"https:\/\/ror.org\/05tewj457","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Triple-negative breast cancer (TNBC) remains a major clinical challenge due to a lack of effective interventions and severe drug resistance. Disrupting tumor metabolism using nitric oxide (NO) donors to drive ferroptosis represents a promising therapeutic strategy. Here, we developed 3A72, a novel furan-coumarin-based NO donor with potent anti-TNBC efficacy.\n                  <jats:italic>In vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  studies demonstrated that 3A72 significantly suppresses TNBC cell proliferation and restricts xenograft tumor growth. Notably, its efficacy matches the first-line drug paclitaxel but with enhanced safety and reduced systemic toxicity.\n                <\/jats:p>\n                <jats:p>\n                  Mechanistically, 3A72 induces ferroptosis in triple negative breast cancer (TNBC) cells via a synergistic dual-pathway mechanism. Initially, 3A72 releases intracellular NO to trigger cytoplasmic calcium overload, followed by high-affinity binding to both inositol 1,4,5-trisphosphate receptor (IP R) and acyl-CoA synthetase long-chain family member 4 (ACSL4). Binding to IP\n                  <jats:sub>3<\/jats:sub>\n                  R provokes mitochondrial calcium overload and a massive burst of reactive oxygen species (ROS), while concurrent ACSL4 activation drives essential membrane phospholipid remodeling. Crucially, our transcriptomic and structural predictions reveal that while ACSL4 exhibits a broader distribution across organelle membranes, its functional association with IP\n                  <jats:sub>3<\/jats:sub>\n                  R spatially converges at the endoplasmic reticulum membranes associated with mitochondria (MAMs). This subcellular niche closely couples IP R-mediated ROS generation with ACSL4-driven lipid remodeling, accelerating lethal malondialdehyde (MDA) accumulation and triggering irreversible ferroptosis. Overall, these findings highlight the MAMs calcium\u2013lipid metabolic hub as a promising structural scaffold for antitumor drug development.\n                <\/jats:p>","DOI":"10.64898\/2026.09.28.754991","type":"posted-content","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T15:45:10Z","timestamp":1791128710000},"source":"Crossref","is-referenced-by-count":0,"title":["A Novel NO Donor 3A72 Activates Mitochondrial-Associated Endoplasmic Reticulum Membrane Structures to Induce Ferroptosis in Triple-Negative Breast Cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1560-5064","authenticated-orcid":false,"given":"Yunke","family":"Long","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, 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