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Novel agents with better tolerability, and efficacy beyond estrogen receptor (ER) positive BC are needed. We studied licochalcone A (LicA) for ER\u2010agnostic BC prevention. We demonstrated that LicA significantly reduced proliferation in seven human breast cell lines and suppressed ER+ and ER\u2212 xenograft tumors in mice. We confirmed these observations ex vivo in the contralateral unaffected breast (CUB) of women with unilateral sporadic BC, and BC cell lines using RNA sequencing, metabolism flux modeling, confirmatory NanoString nCounter metabolic pathway panel analysis in independent sets of specimens, proteomics, and western blots. We found that LicA targets sterol regulatory element binding protein 1 (SREBP1) with subsequent metabolic\u2010inflammatory changes, lowering spatiotemporally resolved cholesterol levels inside malignant cells to the levels in normal mammary cells. Mechanistically, in CUBs we observed that LicA downregulated PI3K\u2010AKT\u2010SREBP1\u2010dependent lipogenesis, NF\u2010kB\u2010dependent inflammation, and de novo nucleotide biosynthesis, stalling proliferation. Studies in cell lines showed suppression of PI3K and AKT phosphorylation, SREBP1 protein expression, and the SREBP1\u2010dependent enzymes such as ACAT2, ACLY, FASN, SCD, consistent with reduced NEDD8 required for SREBP1 stabilization. We found a significant reduction in NF\u2010kB expression, its nuclear translocation mediator karyopherin\n                    <jats:italic>\u03b2<\/jats:italic>\n                    1, and prostaglandin E2 synthesis. We demonstrated a reduction in PRPS1\u2010catalyzed de novo nucleotide biosynthesis, and downregulation of proliferative markers MKI67, RRM2, and the survival marker BCL2. LicA reduces pro\u2010tumorigenic aberrations in lipid homeostasis and inflammation through SREBP1. It is a promising non\u2010endocrine candidate for BC prevention. Future studies in immunocompetent BC prevention models are warranted.\n                  <\/jats:p>","DOI":"10.1002\/ijc.70226","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T04:32:04Z","timestamp":1764304324000},"page":"1927-1940","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Reprogramming\n                    <scp>SREBP1<\/scp>\n                    \u2010dependent lipogenesis and inflammation in high\u2010risk breast with licochalcone A: A novel path to cancer prevention"],"prefix":"10.1002","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0585-5668","authenticated-orcid":false,"given":"Atieh","family":"Hajirahimkhan","sequence":"first","affiliation":[{"name":"Department of Surgery, Feinberg School of Medicine Northwestern University  Chicago Illinois USA"},{"name":"Robert H. 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