Table 6.
Potential therapeutic approaches for alcoholic liver disease by targeting autophagy pathways.
| Drug | Pharmacological Classes | Experimental Model | Main Pathways Involved | Disease Prevention or Potential Benefits |
|---|---|---|---|---|
| AT extract [65] | Flavonoids, phenolic compounds, steroidal glycosides, coumarins. | Intragastric administration of ethanol (5 g/kg b.d., 7 days) or carbon tetrachloride ± AT extract (50 and 150 mg/kg/d) to mice, HepG2 and SK-Hep-1 cells exposed to ethanol. | Induction of autophagy through the activation of Nrf2 and MAPK and increased HO-1 levels. | Reduced liver damage and histopathological changes via increased antioxidant activity. |
| ACE [66] | Basidiomycete triterpenoids, flavonoids, fatty acids, amino acids. |
Administration of white wine (9.52 g/kg, 56°, 2 weeks) and ACE (75, 225, and 675 mg/kg, 2 weeks) to mice. | Reduced Akt/ NF-κB signalling. | Reduced alcohol-induced hepatotoxicity, oxidative stress, and regulation of AST, ALT, oxidation-related enzyme, inflammatory cytokine, and caspase levels. |
| BBD [67] | Traditional Chinese medicine. | Mice gavaged with ethanol (50%, 5 g/kg), pretreated with BBD (0.125, 0.25, and 0.5 g/kg). |
Induction of autophagy through increased NRF2 expression and suppression of CYP450 2E1 induction. | BBD reduced alcohol-induced steatosis, hepatic lipid peroxidation, antioxidant depletion, and oxidative stress. |
| BSE [68] | High levels of flavonoids and polyphenols. | Lieber–DeCarli model for 10 days with intraperitoneal injection of 31.5% ethanol on the last day and BSE (100 and 200 mg/kg/d) gavage, cultured hepatocytes. | Autophagy induction via AMPK activation. | BSE decreased hepatic lipid accumulation and inflammatory macrophage infiltration; in vitro, it induced hepatic β-oxidation and reduced fatty acid synthesis. |
| Calcitriol [69] | Active form of vitamin D. | In vitro, human L02 hepatocytes were pretreated with 100 nM calcitriol, then stimulated acutely with 300 nM ethanol. | Induction of autophagy through the AMPK/mTOR signaling pathway and upregulation of ATG16L1. | Calcitriol alleviated ethanol-induced cytotoxicity and apoptosis caused by oxidative stress and mitochondrial damage in hepatocytes. |
| CBD [70] | Antagonist of CB1/CB2 receptor agonists (negative allosteric modulator of CB1, inverse agonist of CB2). | Mouse acute binge drinking model with intraperitoneal CBD injection (5 mg/kg, q 12 h), HepG2 (E47) cells exposed to ethanol ± CBD. | Induction of autophagy through the blunted activation of the JNK/MAPK pathway. | CBD prevented ethanol-induced autophagy reduction and reduced oxidative stress and acute alcohol-induced liver steatosis in mice. |
| CBZ [47] | Antiepileptic. | Lieber–DeCarli model ± intraperitoneal CBZ (25 mg/kg), chloroquine (60 mg/kg), or rapamycin (2 mg/kg) injection. |
Enhanced mTOR-independent autophagy. | CBZ alleviated hepatic steatosis and liver damage and improved insulin sensitivity. |
| Carvacrol [71] | Monoterpenoid phenol. | Mouse model of acute ethanol intake with carvacrol pretreatment (10 mL/kg). | Induction of autophagy, likely through the inactivation of p38, and inhibition of cytochrome p450. | Carvacrol reduced the TG content and ethanol-induced liver histopathological changes. |
| CMZ [40,72,73] | Thiazole derivative. | Chronic ethanol intake mouse model with CMZ (50 mg/kg), acute ethanol intake mouse model ± CMZ (50 mg/kg). | Induction of autophagy through the activation of the AMPK, MAPK, and PI3K/Akt/GSK3β pathways, and inhibition of CYP2E1. | CMZ suppressed chronic ethanol-induced oxidative stress and pro-inflammatory cytokine production, attenuated acute ethanol-induced fatty liver. |
| Cilostazol [74] | Selective phosphodiesterase III inhibitor. | Acute alcohol intake rat model ± intraperitoneal cilostazol (10 mg/kg/d for 4 days; primary rat hepatocytes were examined. | Autophagy induction via AMPK pathway activation. | Cilostazol protected hepatocytes from apoptosis in vivo and in vitro. |
| Corosolic acid [75] | Pentacyclic triterpene acid extracted from Lagerstroemia speciosa. | Chronic ethanol intake mouse model (intragastric, 60%; 4.5, 6.5, and 9 g/kg/d for 4 weeks) ± corosolic acid (20%, 4 mL b.d., 5–12 weeks). HepG2 cells and BRL-3A liver cells were examined. | Induction of autophagy through the activation of the AMPK pathway and reduction of ROS levels. | Corosolic acid ameliorated alcoholic liver damage, reduced histopathological changes in vivo, and decreased ethanol-induced ROS elevation. |
| DMY [76] | Bioactive flavonoid from Ampelopsis grossedentata. |
Lieber–DeCarli mouse model (1% 2 d, 2% 2 d, 4% 7 d, and 4% 6 weeks) ± oral DMY (75 and 150 mg/kg/d). |
Induction of autophagy through the activation of the Keap-1/Nrf2 pathway and upregulation of p62. | DMY attenuated ethanol induced hepatic enzyme release, lipid peroxidation, TG accumulation, proinflammatory cytokine elevation, and histopathological changes while alleviating IL-1β and IL-6 elevation and pathological changes. |
| TAX [77] | Dihydroflavone. | Acute ethanol intake mouse model (intragastric) ± TAX (1, 5, and 25 mg/kg), HepG2 cells exposed to ethanol and TAX. | Induction of autophagy via AMPK activation and upregulated SIRT1 expression. | TAX reduced liver damage and inhibited alcohol-induced lipid accumulation in mouse livers. |
| Fisetin [78] | Plant polyphenol flavonoid. | Lieber–DeCarli mouse model ± fisetin; human primary HSCs co-cultured with ethanol. | Activation of autophagy through the activation of SIRT1 and inhibition of Sphk1-mediated ER stress. | Fisetin inhibited ER stress and improved alcohol-induced liver damage and fibrosis through the suppression of HSC activation. |
| Fucoidan [79,80] | Long-chain sulfated polysaccharide from various brown algae species. | Mice gavaged with ethanol (56%: 6 [7] mL/kg for 4 weeks then 8 [9] mL/kg for 12 [16] weeks) with daily intragastric fucoidan (100 and 200 [150 and 300] mg/kg). | Induction of autophagy via AMPKα1, SIRT1, and p62/Nrf2/Keap1/SLC7A11 pathway upregulation. | Fucoidan inhibited alcohol-induced steatosis, inflammation, oxidative stress, and histopathological changes; reduced the serum ferritin level; and alleviated liver iron deposition. |
| GMC [81] | Coumarin extracted from licorice. | Chronic and acute ethanol gavage mouse models ± GMC. | Induction of autophagy through the activation of Nrf2 and p38. | GCM prevented acute and chronic ethanol-induced hepatic steatosis in vivo and alleviated oxidative stress. |
| Green tea extract [82] | Tea polyphenols. | Chronic ethanol intake mouse model (50%, 15 mL/kg, intragastric) ± three doses extract (50, 120, and 300 mg tea polyphenols/kg body weight) q.d. for 4 weeks. | Induction of autophagy through increased Nrf2 activation and decreased Keap1 expression. | Dose-dependent improvement of functional and histopathological changes in hepatocytes after ethanol intake. |
| HEPFYGNEGALR (P03) [83] | Peptide isolated from Apostichopus japonicus. | Mice were given one intragastric dose of 50% ethanol (12 mL/kg) after oral P03 (20 mg/kg/d) or spermidine for 35 days and compared with controls without ethanol. |
Induction of autophagy through the activation of the Nrf2/HO-1 pathway and blockade of NF-κB nuclear translocation. | Reduced hepatomegaly, liver inflammation, lipid droplet accumulation and increased antioxidant enzyme activities. |
| KD [84] | Major active ingredient extracted from Anoectochilus roxburghii. | Lieber–DeCarli mouse model ± 5% carbon tetrachloride in olive oil (intraperitoneal injection) and KD (20 40 mg/kg) or silymarin (80 mg/kg); control without ethanol. | Autophagy induction through AMPK activation. | KD alleviated alcoholic liver damage by reducing oxidative stress and lipid accumulation. |
| Lanthanum nitrate [85] | Rare earth element. | Acute ethanol intake mouse model (50%, 12 mL/kg, intragastric) after lanthanum nitrate (0.1, 0.2, 1.0, 2.0, and 20.0 mg/kg) administration for 30 days. |
Induction of autophagy through the activation of the Keap1/Nrf2/p62 pathway. | Improved redox homeostasis and histopathological changes. |
| Melatonin [86] | Pineal gland hormone. | Acute ethanol intake mouse model (0.75 g/kg, intraperitoneal) ± melatonin (10 mg/kg, intraperitoneal) for 10 days. | Improved mitochondrial oxidation of NADH and decreased mitochondrial ability to oxidize FAD. | Prevented lysosomal destruction of liver tissue by limiting the increased activity of lysosomal enzymes and the resulting oxidative stress. |
| NAC [38] | Amino acid modified from L-cysteine. | Acute ethanol intake mouse model. Murine hepatocytes were exposed to ethanol ± NAC. | Reduction of autophagy via mTOR activation and reversed ROS levels. | NAC reduced TG and TBARS contents and ROS stress and reversed ethanol-induced mTOR inhibition. |
| PLT [87] | Protoberberine alkaloid. | Mouse hepatocytes were exposed to 75% alcohol for 2–3 weeks and PLT (0, 20, 50, 100, 150 and 200 μg/mL). | Induction of autophagy via AMPK/mTOR pathway activation. | PLT reduced ethanol-induced liver cell damage by inhibiting hepatocyte apoptosis through autophagy promotion. |
| PCP [88] | Gallic acid, lutein, quercetin, luteolin, apigenin, among others. | Acute ethanol intake (350 mM for 32 h) and/or PCP (100, 50 and 25 μg/mL) with zebrafish larvae. | Induction of autophagy through activating the AMPK/p62/Nrf2/mTOR signaling pathways and reduced oxidative stress. | PCP ameliorated ethanol-induced liver function damage and fat accumulation. |
| Procyanidin [89] | Polyphenol flavonoid. | Acute ethanol intake mouse model ± procyanidin (50 mg/kg for 11 days). | Induction of autophagy through increased LC3-II and reduced p62 levels, reduced ROS levels, and elevated GSH content. | Procyanidin eliminated lipid droplets and damaged mitochondria, thereby reducing hepatic lipid deposition and ROS overproduction. |
| Quercetin [90,91,92,93,94,95] | Plant-derived flavonoid. | Chronic and chronic plus single binge ethanol mouse models ± quercetin (control group without ethanol), L02 cells exposed to 3% ethanol for 24 h plus quercetin (20, 40, and 80 μM) for 24 h (control group without ethanol); transgenic zebrafish larvae were given quercetin (25, 50, and 100 μM for 48 h 3 days after fertilization) and ethanol for 32 h. | Induction of autophagy through FOXO3a activation and reversal of ethanol’s effects on AMPK and ERK2. | Quercetin inhibited inflammation and alleviated chronic ethanol-induced hepatic mitochondrial damage via mitophagy activation. |
| Rapamycin (sirolimus) [15,40,47] | Selective immunosuppressant (mTOR inhibitor). | Chronic and acute ethanol intake mouse models ± rapamycin. | Induction of autophagy via inhibition of mTOR signaling. | Rapamycin reduced ethanol-induced steatosis. |
| Resveratrol [46,96,97] | Dietary polyphenol. | Lieber–DeCarli mouse model plus acute ethanol binge, HepG2 cells exposed to oleic acid and alcohol. | Induction of autophagy via increased sirtuin-1 signaling. | Resveratrol increased the number of autophagosomes, reduced hepatic lipid accumulation, and protected against alcoholic liver steatosis. |
| SaIA [98] | Phenolic carboxylic acid extracted from Salvia miltiorrhiza. | Lieber–DeCarli mouse model with intragastric SaIA (8 and 16 mg/kg/d); AML-12 hepatocytes were examined. | Induction of autophagy via SIRT1 activation. | SaIA restored autophagosome-lysosome fusion, protected the liver from chronic ethanol exposure, decreased transaminase levels, attenuated histopathological liver damage, and prevented ethanol-induced liver cell damage in vitro. |
| Se-SP [99] | Microalga of the cyanobacterial class with chemical element enrichment. | Chronic ethanol intake mouse model (30%, 10 mL/kg by gavage for 15 days) and intragastric Se-SP (100, 200, and 400 mg/kg/d for 42 days). | Reduction of autophagy via decreased LC3 and increased p70s6k expression, and decreased p53, caspase 1, and 3 expression. | Se-SP protected against alcoholic liver damage by increasing antioxidant enzyme levels, inhibiting DNA damage and apoptosis, and inducing pyrosis. |
| Silibinin [100] | Flavonoid glycoside. | HepG2 and HL7702 cells exposed to ethanol or acetaldehyde and silibinin. | Induction of autophagy via PINK1 and Parkin activation. | Silibinin inhibited ethanol-induced ferroptosis, resolved oxidative stress, and reduced iron levels. |
| Simvastatin [101] | Statin. | Chronic ethanol intake rat model ± simvastatin (10 mg/kg/d). | Induction os autophagy, selectively inhibited HMG-CoA reductase. | Simvastatin ameliorated alcohol-induced liver histopathological changes, transaminase elevation, attenuated oxidative stress, and inflammation. |
| Sulforaphane [102] | Isothiocyanate derived from glucoraphanin present in Brassica. | Acute binge drinking mouse model ± sulforaphane (0.05 g/kg for 5 days), HepG2 (E47) cells treated with or without 100 mM ethanol ± 6 uM sulforaphane. | Induction of autophagy via Nrf2 activation. | Sulforaphane prevented binge ethanol–induced oxidative stress and steatosis in CYP2E1 KI mice and lipid accumulation in HepG2 (E47) cells. |
| Tangeretin [103] | Flavonoid derived from citrus peel. | Chronic binge drinking mouse model ± tangeretin (20 and 40 mg/kg). | Induction of autophagy via AMPK/Ulk1 signalling pathway activation. | Tangeretin dose-dependently normalized serum ALT and AST levels, liver weight, and serum and liver triacylglycerol contents; restored mitochondrial respiratory function; and suppressed steatosis. |
| TMP [104] | Alkylpyrazine extracted from Ligusticum wallichii. | Chronic ethanol intake mouse model ± TMP, LO2 cells exposed to ethanol (100 mM) and/or TMP (40 μM for 24 h). | Induction of autophagy via increased UQCRC2 expression and RIPK1/RIPK3 necrosome activation. | Reduced necroptosis and leakage of damage-associated molecular patterns and promoted the clearance of impaired mitochondria. |
| Torin 1 [55,105] | Pyridoquinoline (ATP-competitive mTOR kinase inhibitor). | Chronic plus binge ethanol intake mouse model ± torin 1. | Induction of autophagy via inhibition of mTORC1 and mTORC2 and increased hepatic TFEB levels. | Torin 1 reduced steatosis and liver damage induced by ethanol. |
| UDCA [106] | Hydrophilic bile acid (non–FXR agonistic). | Lieber–DeCarli mouse model ± UDCA. | Attenuated NF-κB activation. | UDCA attenuated and prevented the progression of alcoholic hepatic cholestasis. |
| Zinc (Zn) [107] | Chemical element. | VL-17A cells exposed to 100 mM ethanol for 24 h and 0, 10, 20, and 40 μM Zn for 48 h. | Induction of autophagy via ERK1/2 activation. | Zn depletion significantly suppressed autophagy, Zn exposure stimulated autophagy, cotreatment with ethanol, and 40 μM Zn had an additive effect on autophagy induction. |
AT, Acer tegmentosum Maxim; HO-1, heme oxygenase 1; ACE, Antrodia cinnamomea extract; BBD, Babao Dan; BSE, barley sprout extract; ATG16L1, autophagy-related 16-like 1; CBS, cannabidiol; CBZ, carbamazepine; CMZ, chlormethiazole; PI3K, phosphoinositide 3 kinase; GSK3β, glycogen synthase kinase 3β; DMY, dihydromyricetin; TAX, dihydroquercetin; Sphk1, sphingosine kinase 1; SLC7A11, solute carrier family 7 member 11; GMC, glycycoumarin; HEPFYGNEGALR, histidine–glutamic acid–proline–phenylalanine–tyrosine–glycine–asparagine–glutamic acid–glycine–alanine–leucine–arginine; KD, kinsenoside; NAC, N-acetylcysteine; PLT, palmatine; PCP, Penthorum chinense Pursh; ERK2, extracellular signal–related kinase 2; SalA, salvianolic acid A; SeSP, selenium-enriched Spirulina platensis; HMG-CoA, 3-hydroxy-3- methylglutaryl-coenzyme A; Ulk1, uncoordinated-51-like kinase 1; TMP, tetramethylpyrazine; RIPK1/3, receptor-interacting serine/threonine-protein kinase 1/3; UDCA, ursodeoxycholic acid; Zn, zinc.