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  • Saffron Bioactives as Adjuvant Modulators of Breast-Cancer microRNA Networks

  • Fatemeh Shams,1 Elina Khannehzar,2 Amirsajad jafari,3,*
    1. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
    2. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
    3. Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran; Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran


  • Introduction: Persistent resistance and metastatic spread limit the durability of current breast-cancer therapies. Because a single microRNA (miRNA) regulates dozens of genes, hub miRNAs can function as master switches across survival, metabolism, and invasion circuits. We integrated saffron (Crocus sativus) bioactive targets with breast-cancer miRNA regulation to ask whether saffron could serve as a low-toxicity adjuvant that biases hub-miRNA circuits toward tumor control. Significance : A miRNA-gene network derived from saffron target genes and breast-cancer miRNAs reveals a compact hub architecture dominated by the miR-15/16 family (tumor-suppressive) and oncomiRs (miR-18a-5p, miR-155-5p, miR-9-5p), nominating adjuvant strategies that reinforce apoptosis and blunt metastasis/inflammation.
  • Methods: We unified validated targets of the major saffron constituents and intersected them with breast-cancer–associated miRNAs, yielding an 18-miRNA panel. Validated human miRNA→gene interactions were compiled and restricted to the saffron target union, then analyzed in Cytoscape for degree-based hub identification. Over-representation analysis on miRNA target genes identified GO Biological Processes and pathways. We summarized (i) hub miRNAs, (ii) leading-edge genes within enriched terms, and (iii) overlap with a 14-gene intersection subset prioritized from your network.
  • Results: The filtered network comprised 10 high-degree miRNAs controlling a 68-gene set through hundreds of validated edges. The central control core included miR-16-5p, miR-15a-5p, miR-424-5p, miR-15b-5p, miR-195-5p, miR-497-5p (the miR-15/16 family), and miR-18a-5p, miR-155-5p, miR-9-5p, miR-146b-5p. Enrichment results were concordant with your compound-level analyses and highlighted four dominant axes: 1. Apoptosis/Cell-death control. Genes in the BAD–BCL2 axis and checkpoint nodes were over-represented with high miRNA coverage, consistent with miR-15/16/195/497 repression of anti-apoptotic targets and checkpoint kinases. 2. Migration/EMT/angiogenesis. Positive regulation of cell migration / locomotion terms were significant; oncomiRs miR-9-5p and miR-18a-5p mapped to EMT and Wnt/β-catenin drivers, while saffron-target genes (e.g., FGF2, MYLK) populated these terms. 3. Xenobiotic response/drug transport. Enrichment included ABCB1/ABCG2/ABCC1, aligning with saffron’s capacity to modulate stress and efflux pathways, with the potential to enhance chemosensitivity. 4. Metabolic/pH regulation. Terms related to one-carbon metabolism and pH homeostasis were enriched, reflecting carbonic-anhydrase and redox nodes present in your gene set. Across these axes, 14 intersection proteins were frequently targeted by ≥1 hub miRNA, providing a short list of nodes where adjuvant action is most likely to compound therapeutic effect (e.g., convergence on BCL2/BCL-xL, ABCB1, FGF2). Saffron’s reported anti-inflammatory and pro-apoptotic activities match these network signals, suggesting it can reinforce tumor-suppressive hubs (miR-15/16 family) and antagonize oncomiR circuits (miR-155-driven inflammatory survival programs; miR-9-driven EMT). Discussion/Impact This analysis supports a pragmatic adjuvant framework: Combine apoptosis-inducing therapies (DNA damage, BCL2 inhibition) with saffron bioactives to strengthen the miR-15/16 axis and deepen intrinsic cell-death commitment. Pair anti-proliferative regimens with anti-metastatic leverage by dampening miR-9 / miR-18a pathways (migration, EMT, angiogenesis), where saffron targets (e.g., FGF2, cytoskeletal regulators) already cluster. Address drug resistance by converging on xenobiotic transporters and oxidative-stress buffers that are jointly covered by network miRNAs and saffron targets, aiming to lower effective cytotoxic doses. Given saffron’s safety profile and multi-pathway footprint, the network argues for saffron-anchored adjuvants to (i) reduce metastatic competence, (ii) increase apoptosis, and (iii) mitigate resistance mechanisms,all while preserving tolerability.
  • Conclusion: Saffron bioactives intersect a hub-miRNA regulatory core that governs apoptosis, migration/EMT, xenobiotic handling, and metabolic/pH control in breast cancer. These data justify adjuvant deployment of saffron compounds alongside standard therapies to bias hub circuits toward tumor suppression and to exploit polypharmacology at the miRNA–gene level. Prospective validation should prioritize combinations hitting BCL2-family, FGF/EMT, and ABC-transporter nodes enriched in this network.
  • Keywords: adjuvant therapy; saffron; microRNA hub; apoptosis; drug resistance

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