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Abstract
Background. Luteolin is active in experimental systems. Whether its transcriptional effects reverse those of major depressive disorder (MDD) is unknown.
Objective. To test whether luteolin responses in lipopolysaccharide-exposed systems reverse postmortem dorsolateral prefrontal cortex MDD signatures, and to identify gene- or pathway-level opposition for validation.
Methods. We reanalyzed three luteolin datasets (mouse hippocampus, GSE181285; human neural stem cells, GSE181522; mouse microglia, GSE18740) and two human MDD cohorts (GSE101521 and GSE54568). Technical replicates were aggregated by biological unit. Probes were collapsed independently of outcome. Mouse genes were restricted to one-to-one human orthologs, and effects were combined by random-effects meta-analysis. The primary endpoint was the Spearman correlation between luteolin rescue and MDD effects. We added bootstrap, permutation, distance-to-control, sensitivity, and Reactome analyses.
Results. Across 13,034 shared genes, rescue and MDD effects were weakly and positively correlated (ρ = 0.041, p < 0.001; bootstrap 95% CI 0.023–0.059; permutation p = 0.001). Reversal would have required a negative correlation. Of 302 genes nominally associated in both analyses, 143 (47.35%) were opposed (p = 0.388). Only neural stem cells moved closer to control. Excluding that dataset strengthened the positive correlation (ρ = 0.074); adding MDD-suicide cases weakened it (ρ = 0.004, p = 0.685). No Reactome pathway survived false-discovery-rate correction. Aerobic respiration and electron transport ranked first (q = 0.058).
Conclusion. The integrated evidence does not support global reversal of human MDD transcriptomic signatures by luteolin. Bioenergetic, oxidative, PKA–CREB, glutamatergic, and immune candidates remain targets for hypothesis generation. They need prospective, cell-resolved validation.
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