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Preprint WatchModerateJuly 26th, 2026

Unveiling Gloriosine as a Dual-Acting Regulator of Glutamine Metabolism and Ferroptosis in Triple-Negative Breast Cancer: Insights from Network Pharmacology and Experimental Validation

Dey, B.; Chatterjee, E.; Goel, B.; Jain, S. K.; Naik, P. K.; Guru, S. K.

Network pharmacology and molecular docking nominated SRC, EGFR, mTOR and HSP90AA1 as hub targets of the alkaloid gloriosine in triple-negative breast cancer, with experimental validation showing suppressed glutaminolysis and induction of ferroptosis.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint nominates SRC, EGFR, mTOR and HSP90AA1 as hub targets of the plant alkaloid gloriosine in triple-negative breast cancer using SwissTargetPrediction, TargetNet, PharmMapper and molecular docking, then validates a phenotype of reduced proliferation and migration with suppressed glutaminolysis and induced ferroptosis. The target attribution is computational, and the experimental work measured metabolic and ferroptotic readouts rather than mTOR pathway inhibition, so the mTOR link is a prediction and not a demonstrated mechanism. The Claidex graph carries one mTOR efficacy failure, everolimus-erlotinib-mtor-egfr-pancreatic-cancer-phase2-futility-termination, where an mTORC1-selective rapalog combined with an EGFR inhibitor closed for futility in metastatic pancreatic cancer. A multi-target natural product whose predicted hubs include two targets with logged clinical failures needs direct pathway pharmacodynamics before the target list carries any weight. This flag is recorded for surveillance rather than as a contradiction signal.

Abstract excerpt

Abstract Background TNBC lacks clearly defined molecular targets, so chemotherapy remains the standard approach despite resistance, toxicity, and high relapse rates. New, less toxic therapeutic options are urgently needed. This study evaluated the anticancer potential of gloriosine, a plant-derived alkaloid known to inhibit tumor cell growth with minimal effect on normal breast cells. Methods Putative targets of gloriosine were predicted using SwissTargetPrediction, TargetNet, and PharmMapper, then intersected with gene sets linked to TNBC and glutamine metabolism. The resulting network was characterized through protein-protein interaction mapping and Gene Ontology/KEGG enrichment analysis. Molecular docking assessed binding affinity to top targets, and predictions were validated experimentally using cell viability, colony formation, and wound-healing assays. Oxidative stress and ferroptosis were assessed via ROS (DCFDA), glutathione, and lipid peroxidation (MDA) assays, along with Western blotting and FerroOrange staining. Results Network analysis identified 100 predicted targets, 60 overlapping with TNBC/glutamine-metabolism genes; SRC, EGFR, mTOR, and HSP90AA1 emerged as hub proteins. Enrichment analysis linked this network to cancer progression, metabolic reprogramming, and resistance pathways, including central carbon metabolism and ErbB/EGFR-inhibitor resistance signaling. Docking confirmed strong gloriosine-target binding. Experimentally, gloriosine reduced cell proliferation and migration in a dose-dependent manner. Mechanistically, it suppressed glutaminolysis and induced ferroptosis, marked by increased ROS, glutathione depletion, elevated lipid peroxidation, GPX4 suppression, and intracellular iron accumulation. Conclusions Gloriosine suppresses TNBC growth via multi-target modulation and ferroptosis induction, supporting its potential as a novel anticancer candidate. Keywords: Triple-negative breast cancer (TNBC), gloriosine, network pharmacology, ferroptosis.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.