Background: Amyotrophic lateral sclerosis (ALS) and traumatic brain injury (TBI) are distinct neurological disorders that share overlapping molecular and cellular mechanisms, including neuroinflammation, oxidative stress, and synaptic dysfunction.

Methods: This study employs a systems biology approach to identify common genes and pathways linking ALS and TBI. Differentially expressed genes (DEGs) from publicly available transcriptomic datasets (GSE89866 for TBI and GSE153960 for ALS) were integrated and analyzed through network-based and enrichment analyses. Protein–protein interaction (PPI) networks were constructed to highlight key hub genes and regulatory modules shared between both conditions.

Results: A total of 3885 DEGs were identified in ALS (GSE153960) whereas 449 DEGs were obtained in TBI (GSE89866). Total number of common overlapping DEGs between the two datasets were 20, out of which 13 common DEGs were upregulated in both the cases, while 7 DEGs were downregulated. Important upregulated genes were MAFB, IL13RA1, PLBD1, CYP1B1, FBP1, TLR5, and RAB20. Similarly, key downregulated genes were ZNF541, DNAI2, NYAP1, TRIM17, and TRPV6. The functional enrichment analysis indicated that these key genes are involved largely in the innate immune system, muscle contraction, aldosterone synthesis and secretion, cellular responses to stimuli, cytosolic DNA-sensing pathway and cellular senescence.

Conclusion: These findings provide novel insights into shared molecular mechanisms and may contribute to identifying potential therapeutic targets for neuroprotection and disease modification in ALS and TBI.