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• CVB3 virus infection promoted the inflammatory response, pyroptosis and ROR expression. • Knockdown of ROR relieved CVB3-triggered inflammation and pyroptosis. • ROR damaged the mRNA stability of FOXP1 by binding to PTBP1. • FOXP1 directly repressed NLRP3 transcription. • FOXP1 is involved in the regulatory roles of ROR in CVB3-infected VMC. The purpose of this design was to explore the specific role and related mechanism of long noncoding RNA (lncRNA) regulators of reprogramming (ROR) in viral myocarditis (VMC). AC16 cells were infected with coxsackievirus B3 (CVB3) to establish a VMC cell model in vitro. The release of interleukin (IL)-1β and IL-18 was evaluated by enzyme-linked immunosorbent assay (ELISA). Gene expression was calculated using quantitative real-time (qRT)-PCR. Cell pyroptosis was determined by flow cytometry and Western blot assays. Cell counting Kit-8 (CCK-8) detected cell viability. The molecular associations were verified by employing RNA immunoprecipitation (RIP), RNA pulldown and chromatin immunoprecipitation (ChIP) assays. The lncRNA ROR was more highly expressed in CVB3 virus-infected AC16 cells than in controls. Knockdown of ROR markedly rescued cell viability and reduced the release of IL-1β and IL-18, cell pyroptosis and pyroptotic proteins such as NLRP3, ASC and cleaved caspase 1. Mechanistically, ROR destroyed the mRNA stability of Forkhead Box P Factor 1 (FOXP1) by binding polypyrimidine tract binding protein 1 (PTBP1). FOXP1 repressed the transcription of NLRP3 by directly interacting with its promoter. Importantly, coinhibition of FOXP1 impeded the protective role of ROR silencing in CVB3-infected AC16 cells. In conclusion, these findings elucidated that ROR knockdown inhibited CVB3-induced cardiomyocyte inflammation and NLRP3-mediated pyroptosis by regulating the PTBP1/FOXP1 axis, implying that ROR might be a new inducer in CVB3-infected VMC. [ABSTRACT FROM AUTHOR]