Modulating nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 in liver-brain axis disorders

Figure 1 Structure and function of nuclear factor erythroid 2-related factor 2. Nuclear factor erythroid 2-related factor 2 (Nrf2) is composed of seven conserved Nrf2-ECH homology (Neh) domains, each playing a distinct role in its regulation: Neh1 facilitates antioxidant response element binding via heterodimerization with Maf proteins, Neh2 mediates Kelch-like ECH-associated protein 1 (Keap1)-dependent degradation through ETGE and DLG motifs, and Neh6 enables Keap1-independent degradation via glycogen synthase kinase-3β phosphorylation. Meanwhile, Neh3, Neh4, and Neh5 act as transactivation domains, while Neh7 fine-tunes Nrf2 activity by interacting with retinoid X receptor alpha. Nrf2 serves as a master regulator of cellular health, orchestrating antioxidant defense, metabolic regulation, anti-inflammatory responses, immune homeostasis, protein quality control, and anti-aging mechanisms to ensure cellular adaptation, survival, and longevity. Nrf2: Nuclear factor erythroid 2-related factor 2; NH2: Amino; COOH: Carboxyl; RXR: Retinoid X receptor; GSK-3β: Glycogen synthase kinase-3β; ROS: Reactive oxygen species; RNS: Reactive nitrogen species; SOD: Superoxide dismutase; CAT: Catalase; GPX: Glutathione peroxidase; ATP: Adenosine triphosphate; PGC-1α: Peroxisome proliferator-activated receptor-gamma coactivator-1α; TNF: Tumor necrosis factor; IL: Interleukin; NF-κB: Nuclear factor kappa-B; SHP: Small heterodimer partner.

Figure 2 Enzymatic reaction and function of heme oxygenase-1. Heme oxygenase-1 (HO-1) is a multifaceted enzyme critical for cellular homeostasis, integrating antioxidant defense, immune regulation, vascular protection, and stress adaptation through its degradation products (bilirubin, carbon monoxide, and free iron). HO-1 Leads to the generation of biliverdin, release of carbon monoxide and ferrous iron (Fe²⁺). Biliverdin is transformed into bilirubin by the biliverdin reductase enzyme. Fe²⁺ can be bound by the iron storage protein ferritin. HO-1: Heme oxygenase-1; O₂: Oxygen; NADPH: Nicotinamide adenine dinucleotide phosphate; CO: Carbon monoxide; Fe²⁺: Ferrous iron.

Figure 3 Activation mechanism of the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway: Nuclear factor erythroid 2-related factor 2 is tightly regulated by degradation and stabilization mechanisms. Kelch-like ECH-associated protein 1 (Keap1)-Cul3 mediates nuclear factor erythroid 2-related factor 2 (Nrf2) ubiquitination and degradation, while p62 sequesters Keap1, enhancing Nrf2 accumulation. Glycogen synthase kinase-3β and mitogen-activated protein kinase phosphorylate Nrf2, promoting degradation, whereas protein kinase C, casein kinase 2, protein kinase RNA–like endoplasmic reticulum kinase, c-Jun N-terminal kinase 1, and extracellular regulated protein kinase 1/2 phosphorylation drive Nrf2 nuclear translocation. In the nucleus, Nrf2-sMaf heterodimers bind antioxidant response elements (AREs) to activate transcription. Conversely, Fyn kinase exports Nrf2, and nuclear factor kappa-B compete for ARE binding, suppressing transcription. Acetylation by histone acetyltransferases enhances Nrf2’s DNA binding and transcriptional activity, whereas deacetylation by silent information regulator 1/2 suppresses its activity. Nrf2: Nuclear factor erythroid 2-related factor 2; Keap1: Kelch-like ECH-associated protein 1; GSK-3β: Glycogen synthase kinase-3β; MAPK: Mitogen-activated protein kinase; PKC: Protein kinase C; CK2: Casein kinase 2; PERK: Protein kinase RNA–like endoplasmic reticulum kinase; JNK1: C-Jun N-terminal kinase 1; ERK: Extracellular regulated protein kinase; NF-κB: Nuclear factor kappa-B; AREs: Antioxidant response elements; HATs: Histone acetyltransferases; SIRT: Silent information regulator; HO-1: Heme oxygenase-1; SOD: Superoxide dismutase; CAT: Catalase; GPX: Glutathione peroxidase.

Figure 4 Natural herbal monomers targeting the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway to modulate liver diseases. Monomers extracted from natural herbal ameliorate liver disease through multiple mechanisms, including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, alcoholic liver disease, drug-induced liver injury, hepatitis C virus, liver fibrosis and cirrhosis, and hepatocellular carcinoma. NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; ALD: Alcoholic liver disease; DILI: Drug-induced liver injury; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; Nrf2: Nuclear factor erythroid 2-related factor 2; HO-1: Heme oxygenase-1.