Transcriptomic meta-analysis in plaque psoriasis: an integrative bioinformatic approach to deciphering the genetic landscape and molecular pathways
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Abstract
Psoriasis is a chronic inflammatory skin disease influenced by both genetic and environmental factors. Despite extensive research, its precise etiology remains unclear, posing significant challenges to understanding and treatment. The disease pathogenesis involves self-reactive T cells and immune-related cytokines. Genome-wide association studies have identified various susceptibility loci for immune-related diseases, but the underlying mechanisms remain only partially understood. Recent discoveries of critical signaling pathways, biological processes, and immune cell involvement have expanded our knowledge and offer hope for improved therapeutic strategies.
This study aimed to enhance our understanding of psoriasis and proposes novel therapeutic approaches by employing integrated bioinformatics to identify signaling pathways and biological processes as potential disease markers.
Presenting a systematic review and taking a meta-analytical approach to transcriptomic profiles, this investigation examined differential gene expression patterns across 44 studies involving 975 samples comparing lesional psoriasis, non-lesional psoriasis, and healthy controls. Consensus transcriptome signatures revealed a significant association between immune-related genes and psoriasis pathogenesis. Functional enrichment analysis identified several enriched pathways related to immunity and immune system processes. Comparison of these findings with the existing literature indicated that some immune-related genes were already known, while others are novel in the context of psoriasis. Additionally, novel gene analysis demonstrated psoriasis involvement in pathways such as gluconeogenesis , the FoxO signaling pathway , and mitophagy .
This integrative approach confirmed classic genetic associations while uncovering novel gene expression patterns and pathways relevant to psoriasis. Notably, the disruption of the gluconeogenesis pathway emerged as a critical finding. These insights enhance our understanding of psoriasis pathophysiology and pave the way for targeted therapies, offering improved management options for affected individuals.
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Additionally, it uncovers new genetic and pathway associations implicatedin psoriasis, with particular significance given to the disruption of the gluconeogenesispathway.13.CC-BY-NC 4.0 International licensemade available under a(which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It isThe copyright holder for this preprintthis version posted March 5, 2025.;https://doi.org/10.1101/2025.03.01.640943doi:bioRxiv preprint
Based on your overall discoveries, are you able to generate any specific novel treatment hypotheses for psoriasis that warrant follow-up experimental or clinical testing?
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Because of the close relationship between dysfunctionalautophagy processes and inflammatory skin disorders, some authors have postulated itspotential role as a therapeutic target
This would seem to be consistent with work using rapalogs (which target mTOR, a master regulator of nutrient management, protein synthesis, and autophagy) to treat psoriasis plaques, which was promising (https://doi.org/10.2340/00015555-2724) but has faced challenges due to bioavailability at the site of inflammation.
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Regarding autophag
Autophagy-related processes seem critical. In addition to some of the hypotheses you propose here, is it possible that these differentially expressed genes could impact the secretion of IL-1beta, which undergoes autophagy-mediated secretion?
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Since gluconeogenesis is a metabolicpathway, it may play a role in the utilization of amino acids, which could be released duringprotein breakdown in tissues affected by psoriasis
Amino acid utilization is an interesting hypothesis to explain the putative relationship between gluconeogenesis and psoriasis pathogenesis. Are free amino acids known to be pro-inflammatory?
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