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  • A Pan-Cancer Repurposing Framework for Saffron Bioactives Using Network-Centrality Filtering and cBioPortal Alteration Profiling

  • 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: Natural product drug discovery increasingly emphasizes multi-target agents with systems-level effects, but indication selection remains a key challenge. Crocus sativus (saffron) contains bioactives (kaempferol, crocin/crocetin, and picrocrocin )that engage diverse targets spanning xenobiotic transporters, metabolic enzymes, apoptosis regulators, and hormonal receptors. To prioritize cancers where saffron-derived agents may be most impactful, we developed a pharmacogenomics-style Cancer Repurposing Score (CRS). This score integrates protein–protein interaction (PPI) network centrality with tumor alteration evidence from TCGA datasets accessed via cBioPortal, complemented by druggability annotations.
  • Methods: Methods Target collection and network filtering: A union list of saffron bioactive targets (kaempferol, crocin/crocetin, picrocrocin) was compiled from literature and curated databases (HGNC-standard symbols). The list was mapped onto a cancer protein–protein interaction (PPI) network in Cytoscape. To enrich for biologically influential nodes, degree centrality was applied, and only genes in the top quartile (≥8 interactions) were retained. This hub panel included ESR1, CYP1A1, FGF2, CYP1B1, XDH, MAOA, ABCB1, ABCG2, and NQO1. Tumor evidence mining: Hub genes were queried in cBioPortal across TCGA PanCancer Atlas cohorts. “Cancer Types Summary” profiles provided per-cancer alteration frequencies, including mutation, copy number amplification (CNA), deep deletion, mRNA high/low expression, and protein abundance changes. Scoring framework: For each cancer type d, we defined an Alteration Score as: AlterationScore_d = (1.0 × %Mutation) + (0.8 × %Amplification) + (0.9 × %Deletion) + (0.5 × %mRNA_high) + (0.5 × %mRNA_low) + (0.6 × %Protein_high) + (0.6 × %Protein_low) This score was normalized to 0–1 and weighted by a reliability penalty √(n_d/200) to downscale small cohorts (saturating at 1 for n ≥ 200). To incorporate translational potential, we added a druggability factor equal to the fraction of targets annotated as Tclin/Tchem in Pharos. The final Cancer Repurposing Score was: CRS(d) = 0.85 × AlterationScore_d × √(n_d/200) + 0.15 × Druggability Compound-specific scoring: Identical calculations were performed using compound-specific subsets of targets, enabling a compound × cancer heatmap of saffron constituents.
  • Results: Network filtering: From ~80 initial targets, degree centrality enriched a focused panel of 9–11 hubs, reducing noise while preserving biological breadth. These hubs included efflux pumps (ABCB1, ABCG2), hormone/metabolic regulators (ESR1, CYP1A1, CYP1B1, MAOA), detox enzymes (NQO1, XDH), and growth factors (FGF2). Pan-cancer alteration profiling: ESR1 showed recurrent amplifications and expression shifts, especially in uterine endometrial carcinoma and breast carcinoma. CYP1A1 and CYP1B1 were altered across uterine, cervical, esophageal, lung squamous, and stomach cancers, reflecting metabolic and detoxification footprints. ABCB1/ABCG2 copy number gains appeared in multiple tumors, consistent with drug efflux roles. FGF2 exhibited lower overall alteration rates but recurrent gains in uterine, breast, and lung cancers. Cancer prioritization: Integration of alteration frequencies produced a compact priority set: Uterine corpus endometrial carcinoma (TCGA) Breast carcinoma (TCGA) Skin cutaneous melanoma (TCGA) Stomach adenocarcinoma (TCGA) Lung squamous cell carcinoma (TCGA) These cancers combined high alteration burden with robust cohort size, yielding stable scores. Compound-specific differences: Kaempferol scored highest in breast and uterine cancers, consistent with ESR1 and carbonic anhydrase targeting. Crocin/crocetin preferentially elevated scores in angiogenesis- and migration-heavy tumors (melanoma, cervical, gastric), aligning with FGF/lectin footprints. Picrocrocin contributed strongly in metabolic and pH-linked contexts, supporting its role in microenvironmental modulation. Discussion This hybrid framework demonstrates that filtering saffron bioactive targets by PPI centrality and evaluating their tumor alteration burden produces interpretable, reproducible cancer rankings. The use of cBioPortal ensures the score is anchored directly in TCGA patient evidence, while degree filtering increases specificity by excluding peripheral targets. The compound × cancer map provides a practical guide for: Indication selection: breast, uterine, melanoma, gastric, and lung squamous tumors emerge as high-value opportunities. Constituent tailoring: kaempferol aligns with hormone- and metabolism-driven tumors; crocin/crocetin with angiogenesis; picrocrocin with metabolic/pH regulation. Combination design: enriched hubs such as ESR1, ABC transporters, and detox enzymes suggest synergy with endocrine therapy, efflux modulators, and redox-active agents
  • Conclusion: We present a streamlined, cBioPortal-based Cancer Repurposing Score that integrates network centrality and tumor alteration profiling to prioritize malignancies for saffron bioactive deployment. This framework identifies uterine, breast, melanoma, stomach, and lung squamous cancers as leading indications and separates compound-specific opportunities. The approach is computationally lightweight, biologically interpretable, and generalizable to other natural product mixtures, supporting rational enrichment and translational preclinical design.
  • Keywords: saffron bioactives, kaempferol, crocin, picrocrocin, cancer repurposing, cBioPortal, network central

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