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Microbes & Immunity Big data and DNN-based DTI model in CHP

aberrant inflammatory response to the inhalation of various techniques, we extracted core signaling pathways of CHP
organic antigens. This condition represents a subtype of and non-CHP to identify putative biomarkers, such as
1,2
hypersensitivity pneumonitis, a group of immunologically kinases (e.g., MAPK, PI3K), transcription factors (NF-
mediated disorders caused by sustained exposure to a κB, AP-1), and chemokine receptors (CXCR, CCR), as
diverse array of environmental agents, including animal therapeutic drugs for the treatment of CHP for further
proteins, bacterial and fungal components, and low- validation and drug development efforts. 5
molecular-weight chemical compounds. CHP is a relatively Despite significant advancements in understanding
uncommon disease, with an estimated prevalence ranging CHP, diagnostic challenges persist due to its reliance on
3
from 1.6 to 6.8 cases/100,000 population. The disease multimodal assessment combining clinical evaluation,
can affect individuals of all ages, but it is more commonly radiological interpretation, histopathological findings,
diagnosed in adulthood, with a mean age of onset and exclusion of other interstitial lung diseases. Current
between 50 and 60 years old. Some studies suggest a slight management remains primarily supportive, focusing
predilection for females, although the reasons for this on antigen avoidance and cautious administration of
potential gender difference remain unclear. 1 immunosuppressive agents, such as corticosteroids and
The pathogenesis of CHP is multifactorial, involving antifibrotic therapies. To address this need, our study
2,3
a dysregulated interplay between genetic predisposition, employs a systematic multi-omics approach to elucidate
4
environmental exposures, and immunological the key molecular signaling pathways and biomarkers
dysregulation. Repeated inhalation of the offending implicated in CHP pathogenesis, with the ultimate goal of
antigens leads to the recruitment and activation of various identifying potential therapeutic drug targets. Specifically,
inflammatory cells, including lymphocytes, macrophages, we leveraged large-scale data from transcriptomics,
and neutrophils, within the pulmonary interstitium. proteomics, and interactomics to construct comprehensive
This sustained inflammatory response culminates in systems models, including protein-protein interaction
the formation of non-caseating granulomas, interstitial networks (PPINs), gene regulatory networks (GRNs),
fibrosis, and, ultimately, irreversible lung parenchymal and epigenetic interaction networks (EIN). Furthermore,
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destruction. Through bidirectional RNA sequencing we employed pre-trained deep neural networks (DNNs)
analysis of lung tissue samples from CHP patients, we for drug-target interaction (DTI) prediction, utilizing
trimmed false positives from these networks, yielding established DTI databases coupled with large-scale drug
refined core genome-wide and epigenetic interaction databases to virtually screen for potential multi-target drug
networks (GWGENs). From these curated networks, combinations. These candidate compounds are further
4
6
we identified key dysregulated signaling pathways prioritized based on their pharmacological properties,
associated with the pathogenesis of CHP, such as the including regulatory mechanisms, toxicity profiles, and
mitogen-activated protein kinase (MAPK) signaling target specificities, paving the way for potential drug
pathway, phosphoinositide 3-kinase (PI3K) pathway, and repurposing or de novo design strategies tailored to CHP
chemokine signaling pathways involving the chemokine (Figure 1).
(C-X-C motif) ligand (CXCL)/chemokine (C-X-C motif) Consequently, there is an urgent need for a deeper
receptor (CXCR) and chemokine (C-C motif) ligand comprehension of the intricate molecular mechanisms
(CCL) families. Accumulating evidence implicates these underlying CHP, with the ultimate goal of identifying
5
signaling pathways in the aberrant inflammatory response, novel diagnostic biomarkers and developing targeted
oxidative stress, apoptosis, and fibrosis that characterize therapeutic strategies. In this context, the integration of
CHP. For instance, the dysregulated MAPK signaling systems biology approaches, leveraging large-scale multi-
pathway leads to the altered phosphorylation and activation omics data and network-based modeling, holds significant
of transcription factors such as nuclear factor-kappa B promise in unraveling the complex regulatory networks
(NF-κB), AP-1, and their downstream pro-inflammatory and signaling cascades implicated in CHP pathogenesis.
mediators. Similarly, the PI3K/AKT signaling pathway
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regulates cellular processes such as proliferation, survival, 2. Materials and methods
and metabolism, contributing to lung epithelial cell
dysfunction in CHP. By integrating our systems biology 2.1. Overview of systems biology methods and
methodologies with annotations from curated pathway systemic drug discovery of CHP
databases (e.g., Kyoto Encyclopedia of Genes and Genomes This paper employs a systems biology approach to
[KEGG] pathways), we identified critical nodes and investigate core signaling pathways in CHP and identify
regulatory hubs within these disease-associated signaling significant biomarkers as drug targets, ultimately
pathways. Leveraging principal network projection (PNP) facilitating multi-target drug discovery via DNN-based

Volume 2 Issue 2 (2025) 77 doi: 10.36922/mi.4620