Background/Objectives: Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor that is strongly implicated in various cancers. In its canonical signaling pathway, Janus kinases (JAKs) phosphorylate STAT3 at the Y705 residue in response to cytokines or growth factors, with pY705 serving as a key marker of STAT3 oncogenic activity. Elevated pY705 levels correlate with poor prognosis, and numerous small-molecule inhibitors have been developed to block this phosphorylation site. More recently, phosphorylation at the S727 residue (pS727) has emerged as a critical contributor to STAT3-mediated oncogenesis, particularly due to its role in mitochondrial translocation. Evidence suggests that pS727 may even surpass pY705 in driving oncogenic activity. These findings prompt an important question: Which residue should be prioritized for effective STAT3 inhibition in cancer therapy? Methods: This review compiles and critically analyzes the current literature on STAT3 inhibitors targeting pY705 and/or pS727, evaluating their therapeutic efficacy in vitro, in vivo, and in clinical trials. We assess the unique effects of targeting each residue on downstream signaling, toxicity, and clinical outcomes. Results: Our analysis indicates that inhibitors targeting both pY705 and pS727 achieve the greatest therapeutic effectiveness. However, pS727 targeting is associated with higher toxicity risks. Conclusions: Comprehensive evaluation of STAT3 inhibitors underscores the importance of targeting pY705 for maximum therapeutic benefit. The analysis also shows that co-targeting pS727 may increase overall efficacy. However, pS727 inhibition should be approached with lower affinity to minimize toxicity and enhance the clinical feasibility of dual-targeting strategies.

Background/Objectives: Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor strongly implicated in various cancers. In its canonical signaling pathway, Janus kinases (JAKs) phosphorylate STAT3 at the Y705 residue in response to cytokines or growth factors, with pY705 serving as a key marker of STAT3 oncogenic ac-tivity. Elevated pY705 levels correlate with poor prognosis, and numerous small-molecule inhibitors have been developed to block this phosphorylation site. More recently, phos-phorylation at the S727 residue (pS727) has emerged as a critical contributor to STAT3-mediated oncogenesis, particularly due to its role in mitochondrial translocation. Evidence suggests that pS727 may even surpass pY705 in driving oncogenic activity. These findings prompt an important question: Which residue should be prioritized for ef-fective STAT3 inhibition in cancer therapy? Methods: This review compiles and critically analyzes current literature on STAT3 inhibitors targeting pY705 and/or pS727, evaluating their therapeutic efficacy in vitro, in vivo, and in clinical trials. We assess the unique ef-fects of targeting each residue on downstream signaling, toxicity, and clinical outcomes. Results: Our analysis indicates that inhibitors targeting both pY705 and pS727 achieve the greatest therapeutic effectiveness. However, pS727 targeting is associated with higher tox-icity risks. Conclusions: Comprehensive evaluation of STAT3 inhibitors underscores the importance of targeting both pY705 and pS727 for maximum therapeutic benefit. None-theless, pS727 inhibition should be approached with lower affinity to minimize toxic side effects and enhance the clinical feasibility of dual-targeting strategies.

Anti‐estrogens have had a limited impact on breast cancer (BC) prevention. Novel agents with better tolerability, and efficacy beyond estrogen receptor (ER) positive BC are needed. We studied licochalcone A (LicA) for ER‐agnostic BC prevention. We demonstrated that LicA significantly reduced proliferation in seven human breast cell lines and suppressed ER+ and ER− 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‐inflammatory 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‐AKT‐SREBP1‐dependent lipogenesis, NF‐kB‐dependent 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‐dependent enzymes such as ACAT2, ACLY, FASN, SCD, consistent with reduced NEDD8 required for SREBP1 stabilization. We found a significant reduction in NF‐kB expression, its nuclear translocation mediator karyopherin β 1, and prostaglandin E2 synthesis. We demonstrated a reduction in PRPS1‐catalyzed de novo nucleotide biosynthesis, and downregulation of proliferative markers MKI67, RRM2, and the survival marker BCL2. LicA reduces pro‐tumorigenic aberrations in lipid homeostasis and inflammation through SREBP1. It is a promising non‐endocrine candidate for BC prevention. Future studies in immunocompetent BC prevention models are warranted.