# Timeless and Stainless Alcohol: Concentric Waves from Its Oxidative Metabolism and Related Oxidative Stress

**Authors:** Riccardo Maccioni, Simone Tambaro, Laura Doro, Valentina Bassareo, Alessandra T. Peana, Elio Acquas

PMC · DOI: 10.3390/antiox15020216 · Antioxidants · 2026-02-06

## TL;DR

This review explores how alcohol metabolism causes oxidative stress, leading to cellular damage and diseases like liver cirrhosis and neurodegeneration.

## Contribution

A comprehensive synthesis of alcohol's oxidative metabolism mechanisms and their impact on gene expression, antioxidant systems, and organ-specific pathologies.

## Key findings

- Alcohol metabolism produces acetaldehyde and ROS, which disrupt cellular energy and antioxidant defenses.
- Epigenetic changes and gene polymorphisms contribute to alcohol-induced oxidative stress and diseases like hepatocellular carcinoma.
- Chronic alcohol exposure in the brain is linked to neurodegenerative disorders through oxidative stress and autophagy dysregulation.

## Abstract

Alcohol is a molecule whose multiple effects in living organisms exemplify how profound biological complexity can arise from an exceptionally simple chemical structure interacting with the cellular biochemical machinery. This review was conceived to provide an up-to-date synthesis of the current knowledge on the multifaceted consequences of alcohol oxidative metabolism and alcohol-derived oxidative stress, ranging from disruption of subcellular and cellular homeostasis to impairment of organ function. This study primarily focuses on the consequences of alcohol metabolism and on the mechanisms by which the rise of its main metabolite, acetaldehyde, and of reactive oxygen species (ROS), generates oxidative stress by-products and molecular adducts responsible for compromising cellular energy balance and antioxidant defense mechanisms. In particular, this review aims to provide an exhaustive representation of the mechanisms, causes, and consequences of alcohol oxidative metabolism: this is accomplished by taking into account alcohol-induced modifications of gene expression of cellular antioxidant determinants, the role of epigenetic mechanisms, and that of gene polymorphisms linked to alcohol-dependent oxidative stress and responsible for serious diseases such as, among others, alcoholic hepatitis, cirrhosis, and hepatocellular carcinoma. In addition, this review highlights the role of alcohol oxidative metabolism in the brain, which, in the acute setting, activates the dopaminergic system mainly involved in alcohol reinforcing properties and, upon chronic exposure, contributes to neurodegenerative disorders. Finally, a dedicated paragraph explores autophagy as an integrative mechanism underlying the effects of alcohol-related oxidative stress across multiple organs, including the liver, heart, and brain.

## Linked entities

- **Chemicals:** alcohol (PubChem CID 702), acetaldehyde (PubChem CID 177)
- **Diseases:** alcoholic hepatitis (MONDO:0001505), cirrhosis (MONDO:0005155), hepatocellular carcinoma (MONDO:0007256)

## Full-text entities

- **Genes:** Mir155 (microRNA 155) [NCBI Gene 102465831] {aka rno-mir-155}, COX2 (cytochrome c oxidase subunit II) [NCBI Gene 17709], App (amyloid beta precursor protein) [NCBI Gene 11820] {aka Abeta, Abpp, Adap, Ag, Cvap, E030013M08Rik}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, CXCL8 (C-X-C motif chemokine ligand 8) [NCBI Gene 3576] {aka GCP-1, GCP1, IL8, LECT, LUCT, LYNAP}, Mir21 (microRNA 21) [NCBI Gene 100314000] {aka rno-mir-21}, Ppargc1a (peroxisome proliferative activated receptor, gamma, coactivator 1 alpha) [NCBI Gene 19017] {aka A830037N07Rik, Gm11133, PGC-1, PPARGC-1-alpha, Pgc-1alpha, Pgc1}, Adh1c (alcohol dehydrogenase 1C (class I), gamma polypeptide) [NCBI Gene 24172] {aka Adh, Adh1, Adh1a}, Gsk3b (glycogen synthase kinase 3 beta) [NCBI Gene 56637] {aka 7330414F15Rik, 8430431H08Rik, GSK-3, GSK-3beta, GSK3}, Drosha (drosha ribonuclease III) [NCBI Gene 310159] {aka Etohi2, RGD1307626, Rn3, Rnasen}, Fto (FTO alpha-ketoglutarate dependent dioxygenase) [NCBI Gene 26383] {aka mKIAA1752}, Mettl3 (methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit) [NCBI Gene 56335] {aka 2310024F18Rik, M6A, Spo8}, Il6 (interleukin 6) [NCBI Gene 24498] {aka ILg6, Ifnb2}, Ccl2 (C-C motif chemokine ligand 2) [NCBI Gene 24770] {aka MCP-1, MCP1, Scya2, Sigje}, Ppara (peroxisome proliferator activated receptor alpha) [NCBI Gene 25747] {aka PPAR}, Gpx1 (glutathione peroxidase 1) [NCBI Gene 14775] {aka CGPx, GPx-1, GSHPx-1, Gpx}, Il1b (interleukin 1 beta) [NCBI Gene 24494] {aka IL-1F2}, Nqo1 (NAD(P)H dehydrogenase, quinone 1) [NCBI Gene 18104] {aka Dia4, Dtd, Nmo-1, Nmo1, Nmor1, Ox-1}, Il17a (interleukin 17A) [NCBI Gene 16171] {aka Ctla-8, Ctla8, IL-17, IL-17A, Il17}, Ccl2 (C-C motif chemokine ligand 2) [NCBI Gene 20296] {aka HC11, JE, MCAF, MCP-1, MCP1, SMC-CF}, Tnf (tumor necrosis factor) [NCBI Gene 24835] {aka RATTNF, TNF-alpha, Tnfa}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, Il1b (interleukin 1 beta) [NCBI Gene 16176] {aka IL-1beta, Il-1b}, Cat (catalase) [NCBI Gene 12359] {aka 2210418N07, Cas-1, Cas1, Cs-1}, Mapk8 (mitogen-activated protein kinase 8) [NCBI Gene 26419] {aka JNK, JNK1, Prkm8, SAPK1}, Sirt1 (sirtuin 1) [NCBI Gene 309757] {aka Sir2}, IL1A (interleukin 1 alpha) [NCBI Gene 3552] {aka IL-1 alpha, IL-1A, IL1, IL1-ALPHA, IL1F1}, Mapk14 (mitogen-activated protein kinase 14) [NCBI Gene 26416] {aka CSBP2, Crk1, Csbp1, Mxi2, PRKM14, PRKM15}, Nfe2l2 (nuclear factor, erythroid derived 2, like 2) [NCBI Gene 18024] {aka Nrf2}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, ADH1A (alcohol dehydrogenase 1A (class I), alpha polypeptide) [NCBI Gene 124] {aka ADH1}, Sod1 (superoxide dismutase 1, soluble) [NCBI Gene 20655] {aka B430204E11Rik, Cu/Zn-SOD, CuZnSOD, Ipo-1, Ipo1, SODC}, Aldh3a1 (aldehyde dehydrogenase family 3, subfamily A1) [NCBI Gene 11670] {aka Ahd-4, Ahd4, Aldh, Aldh3}, Tlr9 (toll-like receptor 9) [NCBI Gene 81897], Becn1 (beclin 1, autophagy related) [NCBI Gene 56208] {aka Atg6}, Hmox1 (heme oxygenase 1) [NCBI Gene 15368] {aka D8Wsu38e, HO-1, HO1, Hemox, Hmox, Hsp32}, Sting1 (stimulator of interferon response cGAMP interactor 1) [NCBI Gene 72512] {aka 2610307O08Rik, ERIS, MPYS, Mita, STING, STING-beta}, Gmcl1 (germ cell-less 1, spermatogenesis associated) [NCBI Gene 312516] {aka Gcl}, Cat (catalase) [NCBI Gene 24248] {aka CS1, Cas1, Cat01, Catl, Cs-1}, Keap1 (kelch-like ECH-associated protein 1) [NCBI Gene 50868] {aka INRF2, mKIAA0132}, Ccl3 (C-C motif chemokine ligand 3) [NCBI Gene 20302] {aka G0S19-1, LD78alpha, MIP-1alpha, MIP1-(a), MIP1-alpha, Mip1a}, Ppp2r1a (protein phosphatase 2, regulatory subunit A, alpha) [NCBI Gene 51792] {aka 6330556D22Rik, PP2A, PP2Aa, PR65}, ALDH2 (aldehyde dehydrogenase 2 family member) [NCBI Gene 217] {aka ALDH-E2, ALDHI, ALDM}, Mat1a (methionine adenosyltransferase 1A) [NCBI Gene 11720] {aka AdoMet, Ams, MAT, MATA1, SAMS, SAMS1}, Gapdh (glyceraldehyde-3-phosphate dehydrogenase) [NCBI Gene 14433] {aka Gapd}, Cgas (cyclic GMP-AMP synthase) [NCBI Gene 214763] {aka E330016A19Rik, Mb21d1}, Aldh3a1 (aldehyde dehydrogenase 3 family, member A1) [NCBI Gene 25375] {aka AHDC, Ahd-c, Aldh, Aldh3}, Bace1 (beta-site APP cleaving enzyme 1) [NCBI Gene 23821] {aka ASP2, Bace}, BECN1 (beclin 1) [NCBI Gene 8678] {aka ATG6, VPS30, beclin1}, H2bc1 (H2B clustered histone 1) [NCBI Gene 24829] {aka Hist1h2ba, Th2b, histone}, Mir223 (microRNA 223) [NCBI Gene 100314060] {aka rno-mir-223}, DNMT1 (DNA methyltransferase 1) [NCBI Gene 1786] {aka ADCADN, AIM, CXXC9, DNMT, HSN1E, MCMT}, Rela (Rela proto-oncogene, NFKB subunit) [NCBI Gene 19697] {aka p65, p65 NF-kappa B, p65 NFkB}, Akr1a1 (aldo-keto reductase family 1, member A1) [NCBI Gene 58810] {aka 2610201A18Rik, Akr1a4}, Ppara (peroxisome proliferator activated receptor alpha) [NCBI Gene 19013] {aka 4933429D07Rik, Nr1c1, PPAR-alpha, PPARalpha, Ppar}, Tlr4 (toll-like receptor 4) [NCBI Gene 29260], Ythdf2 (YTH N6-methyladenosine RNA binding protein 2) [NCBI Gene 213541] {aka 9430020E02Rik, HGRG8, NY-REN-2}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, Cyp2e1 (cytochrome P450, family 2, subfamily e, polypeptide 1) [NCBI Gene 13106] {aka CYPIIE1, Cyp2e}
- **Diseases:** cardiomyopathy (MESH:D009202), jaundice (MESH:D007565), Acute kidney injury (MESH:D058186), steatosis (MESH:D005234), tachycardia (MESH:D013610), arrhythmias (MESH:D001145), nausea (MESH:D009325), neurofibrillary tangles (MESH:D055956), narcosis (MESH:D053608), cardiotoxicity (MESH:D066126), acute alcoholic cardiomyopathy (OMIM:610251), mitochondrial abnormalities (MESH:D028361), AUD (MESH:D000437), liver disease (MESH:D008107), left ventricular dilation (MESH:C565277), Inflammatory (MESH:D007249), respiratory infections (MESH:D012141), neurodegeneration (MESH:D019636), injury to (MESH:D014947), cirrhosis (MESH:D005355), alcoholic cardiomyopathy (MESH:D002310), hepatic fibrosis (MESH:D008103), acute pulmonary injury (MESH:D055371), Neuroinflammation (MESH:D000090862), anxiety (MESH:D001007), oesophageal squamous cell carcinoma (MESH:D000077277), chronic kidney disease (MESH:D051436), AD (MESH:D000544), impairment (MESH:D060825), dependence (MESH:D019966), cancer (MESH:D009369), dysbiosis (MESH:D064806), hepatic damage (MESH:D056486), gastrointestinal cancers (MESH:D005770), Cardiac, Renal, and Pulmonary Disorders (MESH:D006331), liver injury (MESH:D017093), amyloid (MESH:C000718787), coronary artery syndrome (MESH:D003324), ALD (MESH:D008108), neuronal death (MESH:D009410), kidney disorders (MESH:D007674), cardiac and kidney failure (MESH:D006333), organ damage (MESH:D000092124), tissue injury (MESH:D017695), cognitive and motor deficits (MESH:D003072), HCC (MESH:D006528), alcohol toxicity (MESH:D019973), cell damage (MESH:D002280), myelin damage (MESH:D020279), Myelin injury (MESH:D003711), pulmonary arterial hypertension (MESH:D000081029), brain damage (MESH:D001925), hypothermia (MESH:D007035), rhabdomyolysis (MESH:D012206), flush reaction (MESH:D005483), OS (MESH:D000079225), astrogliosis (MESH:D005911), cytotoxicity (MESH:D064420), proteinopathies (MESH:D057165), infections (MESH:D007239)
- **Chemicals:** TPCA-1 (MESH:C499326), iron (MESH:D007501), alpha-methyl-p-Tyrosine (MESH:D019805), free fatty acids (MESH:D005230), water (MESH:D014867), cytosine (MESH:D003596), 8-hydroxydeoxyguanosine (MESH:D000080242), cholesterol (MESH:D002784), EtOH (MESH:D000431), S-adenosylhomocysteine (MESH:D012435), aldehydes (MESH:D000447), HO (MESH:D017665), NF (MESH:C038981), D-penicillamine (MESH:D010396), GABA (MESH:D005680), 4-hydroxynonenal (MESH:C027576), glutamate (MESH:D018698), hydroquinones (MESH:D006873), oxygen (MESH:D010100), N6-methyladenosine (MESH:C010223), quinones (MESH:D011809), methionine (MESH:D008715), triglyceride (MESH:D014280), biliverdin (MESH:D001664), carbon (MESH:D002244), lipid peroxides (MESH:D008054), guanine (MESH:D006147), bilirubin (MESH:D001663), carbon monoxide (MESH:D002248), amoxicillin and clavulanate (MESH:D019980), Lipid (MESH:D008055), cysteine (MESH:D003545), minocycline (MESH:D008911), astaxanthin (MESH:C005948), endocannabinoid (MESH:D063388), ATP (MESH:D000255), 3-AT (MESH:D000640), citric acid (MESH:D019343), GSH (MESH:D005978), calcium (MESH:D002118), ROS (MESH:D017382), DA (MESH:D004298), NAD+ (MESH:D009243), morphine (MESH:D009020), acetate (MESH:D000085), N-acetylcysteine (MESH:D000111), Acetaldehyde (MESH:D000079), thiobarbituric acid reactive substances (MESH:D017392), Alcohol (MESH:D000438), 5-Hydroxymethylcytosine (MESH:C011865), rifaximin (MESH:D000078262), O2 - (-), superoxide anion (MESH:D013481), H2O2 (MESH:D006861), sulfasalazine (MESH:D012460), prednisolone (MESH:D011239), disulfiram (MESH:D004221), naltrexone (MESH:D009271), 8-oxoguanine (MESH:C024829), salsolinol (MESH:C036617)
- **Species:** Mus musculus (house mouse, species) [taxon 10090], gut metagenome (species) [taxon 749906], Homo sapiens (human, species) [taxon 9606], Rattus norvegicus (brown rat, species) [taxon 10116]
- **Mutations:** Glu487Lys, glutamate-cysteine

## Full text

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## Figures

5 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12937622/full.md

## References

271 references — full list in the complete paper: https://tomesphere.com/paper/PMC12937622/full.md

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Source: https://tomesphere.com/paper/PMC12937622