Upregulation of ZBTB20 indirectly participate in ferroptosis of Parkinson's disease by neuronal glial interactions.

Parkinson's Disease (PD) is an age- associated late-onset neurodegenerative disorder characterized by typical dysfunction and diverse non-motor complications, which severely impair the quality of life of elderly patients. The present study systematically investigated the biological function, diagnostic value, and underlying molecular mechanisms of zinc finger and BTB domain-containing 20 (ZBTB20) in the pathological progression of PD. Both transcriptional and translational analyses demonstrated significant upregulation of ZBTB20 expression in in vivo PD mouse models and in vitro PD cellular models. Functional cellular experiments revealed that ZBTB20 overexpression markedly promoted mitochondrial reactive oxygen species (ROS) accumulation and aggravated oxidative stress in PD cell lines, whereas ZBTB20 knockdown exerted the opposite protective effects. Consistent with the in vitro observations, in vivo striatal injection of sh-ZBTB20 effectively alleviated pathological lesions and mitigated ROS-mediated oxidative damage in PD mice. Further mechanistic validation from in vitro and in vivo experiments confirmed that ZBTB20 upregulation facilitates ferroptosis during PD progression. Notably, pharmacological activation of ferroptosis completely abolished the motor protective phenotypes induced by ZBTB20 silencing in PD mice, verifying the critical involvement of ferroptosis in ZBTB20-mediated PD pathogenesis. Mechanistic exploration revealed that ZBTB20 knockdown significantly elevated the protein abundance of large tumor suppressor kinase 1 (LATS1) in PD models. Co-immunoprecipitation assays further validated a direct physical interaction between ZBTB20 and LATS1. Specifically, ZBTB20 promotes LATS1 ubiquitination and subsequent proteasomal degradation in vitro. Moreover, pharmacological inhibition of LATS1 effectively reversed the inhibitory effect of ZBTB20 knockdown on microglial ferroptosis in PD models. In conclusion, ZBTB20 exacerbates mitochondrial oxidation- dependent ferroptosis to accelerate PD progression via negatively regulating LATS1 signaling. Targeted inhibition of ZBTB20 therefore represents a promising and actionable therapeutic strategy for the clinical treatment of PD.