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Cardiac fibrosis is a common pathological feature of cardiac remodelling process with disordered expression of multiple genes and eventually lead to heart failure. Emerging evidence suggests that long noncoding RNAs (lncRNAs) have emerged as critical regulators of various biological processes. However, the exact mechanisms of lncRNAs as mediators in cardiac fibrosis have not been fully elucidated. This study aimed to profile the lncRNA expression pattern in human cardiac fibroblasts (HCFs) with cardiac fibrosis. We treated HCFs with transforming growth factor-β (TGF-β) to induce their activation. Then, strand-specific RNA-seq was performed to profile and classify lncRNAs; and perform functional analysis in HCFs. We study the transformation of HCFs with molecular and cell biology methods. Among all identified lncRNA candidates, 176 and 526 lncRNAs were upregulated and downregulated respectively in TGF-β-stimulated HCFs compared with controls. Functional analyses revealed that the target genes of differentially expressed lncRNAs were mainly related to focal adhesion, metabolic pathways, Hippo signaling pathway, PI3K-Akt signaling pathway, regulation of actin cytoskeleton, and hypertrophic cardiomyopathy. As a representative, novel lncRNAs NONHSAG005537 and NONHSAG017620 inhibited the proliferation, migration, invasion, and transformation of HCFs induced by TGF-β. Collectively, our study established the expression signature of lncRNAs in cardiac fibrosis and demonstrated the cardioprotective role of NONHSAG005537 and NONHSAG017620 in cardiac fibrosis, providing a promising target for anti-fibrotic therapy. • We investigated the lncRNA expression profile in cardiac fibrosis with human cardiac fibroblasts. • Strand-specific RNA sequencing was employed to study lncRNAs expression profile. • We confirmed that lncRNAs participated in cardiac fibrosis by bioinformatics analyses. • NONHSAG005537 and NONHSAG017620 attenuates the transformation of human cardiac fibroblasts. • These findings may provide an anti-fibrotic therapy target in cardiac fibrosis. [ABSTRACT FROM AUTHOR]