Mechanism of Shizi Sanhua Decoction on Male Oligospermia Revealed byHerbs-Ingredients and Disease Co-Target Genes Sub-Network

Background: Shizi Sanhua Decoction, a traditional Chinese medicine (TCM) prescription, shows a treatment advantage on male oligospermia. While due to the complexity of the compatibility (multiple herbs composition), the underlying mechanism remains to be deciphered. Methods: Herbs-ingredients-target genes were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and SWISSADME database, intersecting with oligospermia-related derived from DisGeNET to obtain co-target genes. The protein-protein interaction (PPI) network of co-target genes was constructed based on the STRING database, and highly condensed sub-networks and top 10 Hub genes were identified with the CytoHubba plug-in. Herbs, ingredients and KEGG enrichment information were projected onto the identified highly condensed subnetwork to build Herbs-ingredients and disease co-target genes sub-network. Results: After integration of herbs-ingredients-target genes (n=453) with disease genes (n=329), 29 cotarget genes were obtained. Among them, PARP1, AR, CYP17A1, ESR1, ABCB1, STS, CFTR, SOAT1, NR5A1, and HIF1A were related to male infertility (WP4673-WikiPathways). Sub-network analysis further revealed the top 10 Hub genes, and the relation with the herbs and ingredients was demonstrated in the sub-network of herbs-ingredients and disease co-target genes. As expected, reproductive- related biological processes (mammary gland epithelium development, GO:0061180; Oocyte meiosis, hsa04114; Progesterone-mediated oocyte maturation, hsa04914) were enriched. Thyroid hormone signaling pathway (hsa04919), Serotonergic synapse (hsa04726), Chemical carcinogenesisreactive oxygen species (hsa05208), and Endocrine resistance (hsa01522) may contribute to the development of male oligospermia. Conclusion: Constructed herbs-ingredients and disease co-target genes sub-network discloses specific bioprocesses and molecular targets of Shizi Sanhua Decoction in oligospermia treatment.