In this study, we first proposed a CTCF-DPP4 cascade identified by direct binding between CTCF and promoter region of DPP4, whereby CTCF and DPP4 synergistically promoted the pathogenesis of NAFLD through multiple pro-pyroptotic molecules, such regulatory network could be significantly inhibited by treatment with gardenoside. Here, DPP4 is linked to metabolic dysfunction-associated steatotic liver disease.