Poldip2, short for polymerase δ -interacting protein 2, is involved in multiple protein-protein interactions and plays roles in numerous cellular processes. It is associated with pathways such as NF-κB, Rho pathway, and is involved in processes like regulation of the nuclear redox environment, mitochondrial morphology and functions, cell migration and adhesion [4]. It is also a binding partner of DNA polymerase delta, PCNA and some DNA polymerases, suggesting its role in DNA damage response [4].

Heterozygous deletion of Poldip2 protected against LPS-induced blood-brain barrier (BBB) permeability in a sepsis-associated encephalopathy model, with Poldip2+/+ mice showing induction of Poldip2, p65, and Cox-2 before BBB integrity alteration, which was not seen in Poldip2+/- mice [1]. In sepsis-induced lung injury, endothelial-specific Poldip2 knock-out mice (EC-/-) had reduced lung leucocyte infiltration, dampened inflammatory gene expression, and decreased endothelial activation and permeability compared to wild-type littermates (EC + / + ) [2]. Capsaicin treatment or Poldip2 knockdown in diabetic retinopathy models inhibited oxidative stress-related increases in factors like Nox4, VCAM-1, and reduced hyperpermeability [3]. In lung epithelial cells, Poldip2 knockdown suppressed LPS-induced oxidative stress and inflammation via the Nox4/Nrf2/NF-κB signaling pathway [5].

In conclusion, Poldip2 is a multifunctional protein involved in processes like maintaining barrier integrity, regulating oxidative stress and inflammation. Gene knockout mouse models, including heterozygous and endothelial-specific knockouts, have revealed its role in diseases such as sepsis-associated encephalopathy, sepsis-induced lung injury, and diabetic retinopathy, highlighting its potential as a therapeutic target in these disease areas.