en Cardiovascular Physiology/Pharmacology Cardiovascular Physiology/Pharmacology Experimental research article Experimental research article <div style="text-align: justify;"><strong>Introduction: </strong>Tetralogy of Fallot (TOF) is the most common cyanotic form of congenital heart defects. However, there is no effective therapeutic approach and current therapies have limited curative efficacy. Moreover, the exact etiology of TOF has remained largely unknown. Improved understanding of molecular mechanisms can give an insight into TOF pathogenesis and development of therapeutic approaches. <strong>Methods: </strong>Here, we conducted a systematic study on the right ventricular myocardium of 24 infants (16 ToF/8 control) using weighted gene co-expression network analysis (WGCNA) to identify meaningful modules or candidate biomarkers. <strong>Results: </strong>Co-expression network analysis by WGCNA suggested that a highly preserved turquoise module with 2,493 genes and a P-value of 3&times;10-11 was significantly correlated to TOF. The top 5 hub genes of this module were PSMA2, MYL12A, C11ORF71, COMMD6, and CREG1. The result of turquoise module enrichment showed that the most correlation topic in biological processes and KEGG pathways were positive regulation of cardiac neural crest migration involved in outflow tract morphogenesis and positive regulation of neural crest cell differentiation. Also, we recognized 4 FDA-approved drug candidates for other indications could potentially use for the treatment of TOF patients through regulation of two hub genes of the co-expression network (PSMA2 and NDUFA4). Our findings also showed that the 13 experimentally validated microRNAs regulated the co-expression network through 5 hub genes. <strong>Conclusion:</strong> We systematically recognized co-expressed gene modules and hub genes associated with TOF progression, which offered insights into the mechanisms underlying TOF progression and some potential drugs for the treatment of TOF.</div> Congenital Heart Defects, Tetralogy of Fallot, Systems Biology, miRNAs, Drug Repositioning. 298 313 http://ppj.phypha.ir/browse.php?a_code=A-10-324-1&slc_lang=en&sid=1 Hassan Karami 3200319475328460029498 3200319475328460029498 No Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran Maryam Moosavi 3200319475328460029499 3200319475328460029499 No Department of Molecular Medicine, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran Afshin Derakhshani 3200319475328460029500 3200319475328460029500 No Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Ebrahim Miri-Moghaddam 3200319475328460029501 3200319475328460029501 No Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran Marlin Touma 3200319475328460029502 3200319475328460029502 No Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, United States Behzad Baradaran 3200319475328460029503 3200319475328460029503 No Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Nazila Alizadeh 3200319475328460029504 3200319475328460029504 No Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Hossein Mashhadi Abdolahi 3200319475328460029505 3200319475328460029505 No Tabriz Health Services Management Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran Khalil Hajiasgharzadeh hajiasgharzadeh@tbzmed.ac.ir 3200319475328460029506 3200319475328460029506 Yes Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Hossein Safarpour 3200319475328460029507 3200319475328460029507 No Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran