Therapeutic Potential of Cytoglobin and Neuroglobin in Oxidative Stress-Driven Liver Diseases

Chronic liver diseases, including fibrosis and hepatocellular carcinoma (HCC), are primarily driven by oxidative stress, yet traditional antioxidant therapies often lack the specificity and efficacy required for clinical success. This review evaluates the emerging therapeutic potential of two atypical globins, cytoglobin (CYGB) and neuroglobin (NGB), exploring their unique hexacoordinated heme structures that enable potent reactive oxygen and nitrogen species (ROS/RNS) scavenging and redox-regulated signaling. We summarize a broad range of in vitro and in vivo evidence demonstrating that these globins deactivate hepatic stellate cells, reduce extracellular matrix accumulation, and function as tumor suppressors by modulating pathways such as Raf/MEK/ERK and NRF2. In human cohorts, CYGB expression levels inversely correlate with the progression of Metabolic Dysfunction-Associated Steatohepatitis (MASH) and HCC, highlighting its potential as a clinical biomarker. Furthermore, recombinant protein therapies involving CYGB and NGB show promise in promoting collagen degradation and inhibiting malignant transformation. We conclude that CYGB and NGB represent sophisticated catalytic redox regulators that offer a novel therapeutic paradigm for restoring redox homeostasis. While delivery and pharmacokinetic barriers remain, these globins are highly promising candidates for first-in-class biologics in hepatology.