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Integrative transcriptomic analysis and explainable machine learning reveal the potential mechanisms of acupuncture
1LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
Background:
Acupuncture has shown clinical benefits in Crohn's disease (CD), but the molecular links between acupuncture-responsive endogenous mediators and CD-related targets remain unclear.
Methods:
We integrated literature-derived acupuncture-responsive endogenous mediators with transcriptomic data from the Gene Expression Omnibus (GEO). Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were used to identify CD-associated signature genes, which were intersected with predicted mediator targets. Eight machine-learning algorithms with repeated nested cross-validation and independent external validation were used to prioritize candidate targets, followed by SHapley Additive exPlanations (SHAP) interpretation. Immune-cell composition was estimated using Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT), and molecular docking was performed between the prioritized target and acupuncture-responsive endogenous mediators.
Results:
Ten acupuncture-responsive endogenous mediators and six shared candidate targets were identified. Random forest (RF) achieved the highest mean area under the receiver operating characteristic curve (AUC) in repeated nested cross-validation (0.905 ± 0.008), whereas gradient boosting machine (GBM) showed the highest AUC in the independent validation cohort, with an AUC of 0.789 and a 95% confidence interval (CI) of 0.652-0.925. FER ranked among the top three features in all eight models and showed the highest mean absolute SHAP value (0.267). FER expression was positively correlated with neutrophil abundance (ρ=0.268, P < 0.001) and negatively correlated with M2 macrophage abundance (ρ=-0.265, P < 0.001). Among the ten endogenous mediators examined, corticosterone showed the most favorable predicted docking score with the FER Src homology 2 (SH2) domain (-6.53 kcal/mol).
Conclusion:
FER emerged as the prioritized target and was associated with neutrophil and M2 macrophage abundance. The predicted structural compatibility between corticosterone and the FER SH2 domain provides a testable hypothesis for future studies of acupuncture-responsive endogenous mediators in CD.