ABSTRACT: Heart failure is mainly caused by a decline in the systolic function of the heart. LncRNAs are related to cardiac diseases. This study aimed to explore the effects of lncRNA testis development related gene 1 (TDRG1) on the fibrogenesis and inflammatory response of transforming growth factor-beta1 (TGF-β1)-stimulated human cardiac fibroblasts (HCFs). Levels of proinflammatory cytokines were evaluated by ELISA. RT-qPCR was applied to reveal the expression levels of TDRG1, miR-605-3p and TNFRSF21. Western blot analysis was prepared to detect protein levels of TNFRSF21 and fibrosis related genes. Luciferase reporter assay was conducted for confirming the interaction between miR-605-3p and TDRG1/TNFRSF21. We found that TGF-β1-stimulated HCFs showed high concentrations of proinflammatory cytokines, and increased protein levels of fibrosis related genes, suggesting the dysfunctions of TGF-β1-stimulated HCFs. In addition, TDRG1 was upregulated in TGF-β1-stimulated HCFs. We found that interfering with TDRG1 alleviated dysfunctions of TGF-β1-stimulated HCFs. Moreover, TDRG1 bound with miR-605-3p. MiR-605-3p exerted the anti-fibrogenic and anti-inflammatory effects in TGF-β1-treated HCFs. As a target gene of miR-605-3p, TNFRSF21, reversed the anti-fibrogenic and anti-inflammatory effects of TDRG1 knockdown in TGF-β1-treated HCFs. Overall, our study confirmed that TDRG1 aggravates fibrogenesis and inflammatory response in TGF-β1-treated HCFs via the miR-605-3p/TNFRSF21 axis.