Integrated transcriptomic profiling implicates MAPK14/p38α as a candidate shared molecular target at the...

Sepsis and postoperative delirium (POD) may share inflammatory and neuroimmune mechanisms, but their common molecular basis remains unclear. This study aimed to identify candidate shared molecular targets and explore a clinically feasible pharmacological candidate linked to the prioritized target.

Multi-cohort transcriptomic data from the Gene Expression Omnibus were integrated. Marked test-statistic inflation in the sepsis discovery cohort GSE65682 was addressed using a Removal of Unwanted Variation 2 (RUV2)-style adjustment based on the 10% lowest-variance genes and four estimated unwanted factors. Transcriptome-wide directional concordance between sepsis and POD was assessed using a rank-rank hypergeometric overlap-like analysis. Separately, RUV2-corrected sepsis differentially expressed genes were intersected with nominally significant POD candidate genes, and directionally concordant genes underwent functional-enrichment and protein-protein interaction analyses. Candidate genes retained from the protein-protein interaction (PPI) network analysis were further evaluated through cross-cohort expression analysis and SHAP-based feature importance analysis. Following target prioritization, target-guided pharmacological assessment, molecular docking, and immune-cell signature analysis were performed.

RUV2-style adjustment reduced the genomic inflation factor in GSE65682 from 41.49 to 6.09, although residual inflation remained. The corrected analysis identified 440 sepsis-associated differentially expressed genes. Forty-four genes overlapped with the exploratory POD candidate set, of which 22 showed concordant directions of change. PPI analysis identified seven network-connected candidates. MAPK14 showed consistent disease-associated upregulation across the sepsis discovery cohort, an independent sepsis cohort, and the POD cohort, and had the highest SHAP contribution. Following prioritization of MAPK14, pharmacological candidates linked to this target were evaluated, leading to the selection of losartan as a clinically feasible candidate for exploratory assessment. Molecular docking suggested structural plausibility but did not establish direct binding or functional inhibition. MAPK14 expression was also positively associated with a neutrophil-predominant immune signature.

These findings implicate MAPK14/p38α as a candidate shared molecular target between sepsis and POD. The losartan-MAPK14 association remains computational and hypothesis-generating and requires experimental and prospective clinical validation.