ABSTRACT: Background: Cardiac fibrosis (CF) and heart failure (HF) are familiar heart diseases that are harmful to health, and severe CF can lead to HF. In this study, we tried to find their common potential molecular markers, which may help the diagnosis and treatment of CF and HF. Methods: Firstly, RNA library construction and high-throughput sequencing were performed. In addition, the DESeq2 package in R was used to screen genes with differentially expressed between different samples. Then, take the intersection of the differential mRNA, miRNA and lncRNA obtained for the two diseases. Thirdly, the ConsensusPathDB (CPDB) was used to perform biological functions enrichment for intersection differentially expressed mRNAs (DEmRNAs). Fourthly, construct gene interaction network and screen out key genes. Fifthly, RT-PCR verification was performed. Lastly, GSE104150 and GSE21125 data sets were utilized to validation the expression and diagnostic analysis. Results: There are 1477 DEmRNAs, 502 differentially expressed lncRNA (DElncRNAs) and 36 differentially expressed miRNA (DEmiRNAs) between CF and healthy control group. There are 607 DEmRNAs, 379 DElncRNAs and 42 DEmiRNAs between HF and healthy control group. CH and FH shared 146 DEmRNAs, 80 DElncRNAs, and 6 DEmiRNAs. Hsa-miR-144-3p, CCNE2, C9orf72, MAP3K20-AS1, LEF1-AS1, AC243772.2, FLJ46284 and AC239798.2 were keys genes in lncRNA-miRNA-mRNA network. In addition, hsa-miR-144-3p and CCNE2 may be considered as potential diagnostic gene biomarkers in CF and HF.