Background: The double stranded RNA (dsRNA)-activated protein kinase PKR is a well-established
protein kinase that is activated by dsRNA during viral infection, and it inhibits global protein synthesis by phosphorylating
the alpha subunit of eukaryotic initiation factor 2 (eIF2). Recent studies have greatly broadened the
recognized physiological activities of PKR by demonstrating its fundamental role in inflammatory signaling, particularly
in chronic, low-grade inflammation induced by metabolic disorders, known as metaflammation.
Metaflammation is initiated by the activation of the NOD-like receptor (NLR), leucine-rich repeat, pyrin domaincontaining
3 (NLRP3) gene by mitochondrial reactive oxygen species (ROS). A protein complex defined as the
metaflammasome is assembled in the course of metaflammation. This complex integrates nutritional signaling with
cellular stress, inflammatory components, and insulin action and is essential in maintaining metabolic homeostasis.
PKR is a key constituent of the metaflammasome and interacts directly with several inflammatory kinases, such as inhibitor B (IB)
kinase (IKK) and c-Jun N-terminal kinase (JNK), insulin receptor substrate 1 (IRS1), and component of the translational machinery such
as eIF2. Conclusion: This review highlights recent findings in PKR-mediated metaflammation and its association with the onset of
metabolic syndrome in both human and animal models, with a focus on the molecular and biochemical pathways that underlie the progression
of obesity, insulin resistance, and type-2 diabetes.