Computational biology and chemistry · 2026
Multilayer human data prioritise RAF-MEK-ERK/MAPK3 as a candidate signalling axis of depressive disorder relevance within the target landscape of Gegen Qinlian Decoction.
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Gao Zixiang, Li Xiang, Zhou Xianqi, Zhou Zixuan, Li Zining
Аннотация
BACKGROUND: Gegen Qinlian Decoction (GQD) has shown preclinical antidepressant-like effects, but the disease-relevant signalling architecture of its putative targets remains unclear.
AIMS: We aimed to prioritise a candidate signalling axis connecting putative GQD targets with depressive disorder-related human molecular evidence.
METHODS: Putative GQD targets were integrated with disease knowledgebases, blood transcriptomics, co-expression analysis, Mendelian randomisation, protein-protein interaction topology and single-nucleus transcriptomics of the human prefrontal cortex. Robustness was evaluated by target-selection sensitivity, six-cohort random-effects meta-analysis, evidence-layer ablation, virtual knockout and leakage-controlled model benchmarking. Docking and molecular dynamics assessed structural plausibility.
RESULTS: RAF-MEK-ERK signalling showed the most consistent cross-layer convergence. MAPK and Ras pathway enrichment remained stable across target-selection criteria, whereas individual predicted targets were sensitive to the probability threshold. BRAF, MAP2K1 and MAPK3 were prioritised, with MAPK3 remaining uniquely or jointly top-ranked after omission of each evidence layer. Single-nucleus analyses localised the candidate axis predominantly to neuronal populations. Across six major depressive disorder cohorts (n = 511), MAPK3 showed no significant pooled expression difference (logFC = 0.120; 95% CI, -0.001-0.241; FDR = 0.976). The three-gene model achieved the numerically highest pooled external AUC (0.561; 95% CI, 0.496-0.627; 22-gene panel, 0.502), but the difference was not significant after correction (FDR = 0.144).
CONCLUSIONS: Multilayer evidence prioritised RAF-MEK-ERK/MAPK3 within the putative target landscape of GQD. The findings support a focused experimental hypothesis but do not establish direct pharmacological regulation, mechanistic causality or clinical utility.
AIMS: We aimed to prioritise a candidate signalling axis connecting putative GQD targets with depressive disorder-related human molecular evidence.
METHODS: Putative GQD targets were integrated with disease knowledgebases, blood transcriptomics, co-expression analysis, Mendelian randomisation, protein-protein interaction topology and single-nucleus transcriptomics of the human prefrontal cortex. Robustness was evaluated by target-selection sensitivity, six-cohort random-effects meta-analysis, evidence-layer ablation, virtual knockout and leakage-controlled model benchmarking. Docking and molecular dynamics assessed structural plausibility.
RESULTS: RAF-MEK-ERK signalling showed the most consistent cross-layer convergence. MAPK and Ras pathway enrichment remained stable across target-selection criteria, whereas individual predicted targets were sensitive to the probability threshold. BRAF, MAP2K1 and MAPK3 were prioritised, with MAPK3 remaining uniquely or jointly top-ranked after omission of each evidence layer. Single-nucleus analyses localised the candidate axis predominantly to neuronal populations. Across six major depressive disorder cohorts (n = 511), MAPK3 showed no significant pooled expression difference (logFC = 0.120; 95% CI, -0.001-0.241; FDR = 0.976). The three-gene model achieved the numerically highest pooled external AUC (0.561; 95% CI, 0.496-0.627; 22-gene panel, 0.502), but the difference was not significant after correction (FDR = 0.144).
CONCLUSIONS: Multilayer evidence prioritised RAF-MEK-ERK/MAPK3 within the putative target landscape of GQD. The findings support a focused experimental hypothesis but do not establish direct pharmacological regulation, mechanistic causality or clinical utility.