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

Table 1 Natural monomers modulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway to mitigate non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

Monomers	Disease models	Mechanisms	Role	Ref.
Quercetin	NAFLD	Regulates hepatic lipid metabolism, oxidative stress and inflammatory response	Improve	Bender et al[94]
Silymarin	NASH	Suppresses HSCs activation and TNF-α	Improve	Keum[95]
Berberine	NAFLD	Regulates lipid metabolism and inflammation	Improve	Cominacini et al[96]
Ginsenoside	NAFLD	Prevent lipid accumulation and oxidative damage	Improve	Abdalkader et al[97]
Capillin	NASH	Mitigates hepatocyte apoptosis, lipid accumulation, and oxidative damage	Improve	Björnsson and Björnsson[98]
Baicalin	NASH	Modulates mitochondrial function, suppresses pyroptosis	Improve	Rousta et al[99]
Aloin	NASH	Antioxidant, anti-inflammatory, and anti-apoptotic	Improve	Emad et al[100]
Flavones	NASH	Attenuates oxidative stress and liver inflammation	Improve	Zhai et al[101]
Linalool	NAFLD	Suppresses lipid accumulation and oxidative stress	Improve	Jin et al[102]
Wogonoside	NAFLD	Antioxidant, anti-inflammatory	Improve	Gao et al[103]
Scutellarin	NAFLD	Reduces oxidative stress, improves hepatic function	Improve	Pan et al[104]; Li et al[105]
Naringin	NAFLD	Suppresses NF-κB/TNF-α axis and triglyceride synthesis	Improve	Wu et al[106]
Geniposide	NAFLD	Reduces lipid accumulation	Improve	Shen et al[18]
Dehydroabietic acid	NAFLD	Inhibits ROS accumulation and MDA levels	Improve	Liu and Hou[107]

NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; HSC: Hepatic stellate cell; NF-κB: Nuclear factor kappa-B; TNF: Tumor necrosis factor; ROS: Reactive oxygen species; MDA: Malondialdehyde.

Table 2 Natural monomers modulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway to mitigate alcoholic liver disease

Monomers	Disease models	Mechanisms	Role	Ref.
Quercetin	ALD	Induces p62 expression, inhibits the binding of Keap1 to Nrf2	Improve	Tseng et al[116]
Silymarin	ALD	Reduces TGF-β1 and 4-HYP levels, suppressing oxidative injury	Improve	Chen et al[117]
Curcumin	ALD	Suppress p53 expression, enhances Nrf2 nuclear translocation	Improve	Yu et al[118]
Ginsenosides	ALD	Reduces oxidative stress and liver inflammation	Improve	Chen et al[119]
Baicalin	ALD	Antioxidant and anti-inflammatory	Improve	Yang et al[120]
Polysaccharides	ALD	Regulating oxidative stress and improve alcoholic liver injury by inhibiting the production of inflammatory factors	Improve	Roehlen et al[121]
Oleanolic acid	ALD	Suppress the alcohol-induced increases	Improve	Zhang et al[122]
CAE	ALD	Antioxidant, anti-inflammatory, and anti-apoptotic	Improve	Parola and Pinzani[123]

CAE: Citrus aurantium extract; ALD: Alcoholic liver disease; Nrf2: Nuclear factor erythroid 2-related factor 2; Keap1: Kelch-like ECH-associated protein 1; TGF-β1: Transforming growth factor-β1; 4-HYP: Hydroxyproline.

Table 3 Natural monomers modulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway to mitigate drug-induced liver injury

Monomers	Disease models	Mechanisms	Role	Ref.
Isorhamnetin	DILI	Reduces oxidative stress, inflammation, and pyroptosis	Improve	Forner et al[134]
Dihydromyricetin	DILI	Reduces apoptosis and oxidative stress	Improve	Ganesan and Kulik[135]
Curcumin	DILI	Alleviate hepatic inflammation	Improve	Yang et al[136]
Berberine	DILI	Alleviate hepatic inflammation	Improve
Resveratrol	DILI	Mitigate oxidative stress, and mitochondrial dysfunction	Improve	Xu et al[137]
Ginsenosides	DILI	Reduces apoptosis and ROS	Improve	Hayes and McMahon[138]
Andrographolide	DILI	Decreases MDA and ROS	Improve	Hallis et al[139]
Astragaloside IV	DILI	Reduces inflammation	Improve	Loboda et al[140]
Salvianolic acid C	DILI	Attenuates oxidative stress, inflammation, and apoptosis	Improve	Lohitesh et al[141]

DILI: Drug-induced liver injury; ROS: Reactive oxygen species; MDA: Malondialdehyde.

Table 4 Natural monomers modulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway to mitigate hepatitis C virus

Monomers	Disease models	Mechanisms	Role	Ref.
Andrographolide	HCV	Increases biliverdin levels	Improve	Narożna et al[150]
Celastrol	HCV	Enhances antiviral interferon responses, suppresses NS3/4A protease activity	Improve	Hassan et al[151]
Lucidone	HCV	Increases biliverdin levels	Improve	Sun et al[152]
Sulforaphane	HCV	Enhances IFN responses, suppresses NS3 protease activity	Improve	Fu et al[153]
Curcumin	HCV	Induces HO-1, inhibits PI3-AKT pathway	Improve	Chopra and Dhingra[154]

HCV: Hepatitis C virus; NS: Nonstructural; IFN: Interferon; HO-1: Heme oxygenase-1; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B.

Table 5 Natural monomers modulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway to mitigate liver fibrosis and cirrhosis

Monomers	Disease models	Mechanisms	Role	Ref.
Curcumin	Cirrhosis	Reduces collagen I deposition	Improve	Yatoo et al[162]
Curcumin	Fibrosis	Reduces oxidative stress, inflammatory and fibrotic markers	Improve	Sailo et al[163]
Pomegranate extract	Fibrosis	Reduces oxidative stress, inflammatory and fibrotic markers	Improve	Sailo et al[163]
Hyperoside	Fibrosis	Reduces oxidative stress, restores antioxidant enzyme activities	Improve	Manawy et al[164]
Schisandrin B	Fibrosis	Mitigates oxidative stress, suppresses HSC activation	Improve	Robledinos-Antón et al[165]
Tanshinol	Fibrosis	Reduces oxidative stress, MDA, inflammatory	Improve	Kundrapu and Malla[166]
Salvianolic acid A	Fibrosis	Inhibits inflammation and oxidative stress	Improve	Wu et al[167]
Asiatic acid	Fibrosis	Reduces oxidative stress	Improve	Wang et al[168]

HSC: Hepatic stellate cell; MDA: Malondialdehyde.

Table 6 Natural monomers modulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway to mitigate hepatocellular carcinoma

Monomers	Disease models	Mechanisms	Role	Ref.
Curcumin	HCC	Reduces oxidative damage and inflammation	Improve	Khalil et al[178]
Resveratrol	HCC	Against oxidative stress	Improve	Amirshahrokhi and Niapour[179]
Berberine	HCC	Reduces hepatic triglyceride accumulation and oxidative stress	Improve	Bellaver et al[181]
Tanshinone IIA	HCC	Reduces oxidative stress markers and enhances antioxidant defenses	Improve	Zhao et al[182]
Ginsenosides	HCC	Inhibits inflammasomes	Improve	Gao et al[183]
Brusatol	HCC	Mediates ferroptosis	Improve	Görg et al[184]
Oleanolic acid oxime derivatives	HCC	Reduces cell cycle, apoptosis, and proliferation	Improve	Navarro and Esteras[185]
Emodin	HCC	Suppresses cell proliferation, invasion, and angiogenesis	Improve	Wang et al[186]

HCC: Hepatocellular carcinoma.