Poldip2, short for polymerase δ-interacting protein 2, is involved in multiple protein-protein interactions and plays roles in various cellular processes. It participates in regulating the nuclear redox environment, organization of the mitotic spindle, chromosome segregation, pre-mRNA processing, mitochondrial morphology and functions, cell migration, and cellular adhesion. It is also associated with DNA damage response as a binding partner of high-fidelity DNA polymerase delta, PCNA, and some translesion and repair DNA polymerases [4].

In sepsis-associated encephalopathy, heterozygous deletion of Poldip2 protected against lipopolysaccharide (LPS)-induced blood-brain barrier (BBB) permeability. Poldip2 mediated LPS-induced BBB disruption by regulating NF-κΒ subunit p65 activation and Cox-2 and prostaglandin E2 induction [1].

In sepsis-induced lung injury, endothelial-specific Poldip2 knockout mice showed reduced lung leucocyte infiltration, dampened induction of inflammatory gene expression, and decreased endothelial activation and permeability. Poldip2 regulated sepsis-induced lung injury via Rho pathway activation [2].

In diabetic retinopathy, capsaicin treatment or Poldip2 knockdown inhibited oxidative stress-related increases, like ROS production and hyperpermeability. Capsaicin may act by suppressing the PPARγ-poldip2-Nox4 pathway [3].

In LPS-induced oxidative stress and inflammation in human lung epithelial cells, Poldip2 mediated these effects via interaction with Nox4 and was regulated by the PI3K-AKT signaling. Poldip2 knockdown also protected against LPS-induced acute lung injury via the Nox4/Nrf2/NF-κB signaling pathway [5,6].

In conclusion, Poldip2 is a multifunctional protein involved in various biological processes. Gene knockout models, such as in sepsis-associated encephalopathy, sepsis-induced lung injury, and diabetic retinopathy, have revealed its role in processes like inflammation, oxidative stress, and barrier disruption. These findings suggest that targeted inhibition of Poldip2 may provide clinical benefits in preventing related disease-induced damages.