LncRNA PVT1 mediates the progression of liver necroptosis via ZBP1 promoter methylation under nonylphenol exposure

Nonylphenol (NP) is one of the most toxic and ubiquitously present endocrine disrupting compounds. Numerous studies have shown that NP exposure induces liver injury, but the interactions between epigenetic factors and necroptosis in this context have not been examined. In this study, rats received daily NP administration (15, 45, and 135 mg/kg/day) via oral gavage over a 28-day period. The upregulation of lncRNA PVT1 was associated with the elevated expression of necroptosis-related proteins (ZBP1, RIPK3, MLKL, and p-MLKL). Moreover, similar effects were also observed after NP exposure in BRL-3A cells. LncRNA PVT1 was predominantly expressed in the nucleus, and ASO was chosen to knock down lncRNA PVT1 in BRL-3A cells. Experimental techniques such as RNA immunoprecipitation, chromatin immunoprecipitation, and co-immunoprecipitation were used to verify direct binding interactions among lncRNA PVT1, EZH2, DNMT1, and ZBP1. The evidence obtained indicated that lncRNA PVT1 could bind to DNMT1 via EZH2 and increase methylation at the ZBP1 promoter, thereby promoting necroptosis. Meanwhile, the demethylation of the highly expressed gene TET1 also promoted ZBP1 upregulation, inducing necroptosis. Taken together, these findings provide valuable insights into the potential molecular mechanisms underlying liver injury in response to NP exposure. Hence, they lay a mechanistic foundation for the evaluation of NP biosafety.