Smoking-induced liver injury and related diseases: Molecular mechanisms, pathogenic amplification, and clinical implications

Table 1 Summary of clinical and mechanistic evidence on smoking-related exacerbation of liver diseases

Disease	Strength of clinical evidence	Clinical reference	Depth of mechanistic evidence	Mechanistic reference
HBV	Level 1	Large observational cohorts report impaired HBV vaccine antibody persistence and a positive association between smoking and HBV-related HCC risk[11,12]	Level 1	Animal and in vitro studies suggest sustained ROS, IL-33-Treg-mediated inflammation, and enhanced fibrotic/carcinogenic signaling[13-15]
HCV	Level 1	Meta-analyses of observational studies report reduced antiviral treatment response and elevated HCV-related HCC risk[12,16]	Level 1	Animal and in vitro studies suggest augmented HCV-induced oxidative stress with incomplete downstream mechanistic mapping[13]
MASLD	Level 1	MR analyses using genetic instruments for smoking exposure suggest a potential causal relation with MASLD, while meta-analyses of observational studies report a positive relation with MASLD risk[17,18]	Level 1	Animal and in vitro studies suggest ROS-driven metabolic disruption, gut dysbiosis, and enhanced fibrogenic activation[7,19]
ALD	Level 1	Meta-analyses of observational studies report a higher ALD risk independent of alcohol consumption level[20]	Level 1	Animal and in vitro studies suggest synergistic oxidative, ER stress and impaired hepatic regeneration under combined smoking-alcohol exposure[21]
PBC	Level 2	Meta-analyses of case-control and cross-sectional studies indicate an relation between smoking and higher PBC incidence as well as more rapid progression to advanced fibrosis[22,23]	Level 3	Mechanistic evidence linking smoking to PBC pathogenesis remains scarce
PSC	Level 2	Meta-analyses of case-control studies report an inverse relation between smoking and PSC incidence[24]	Level 3	Mechanistic explanations for the inverse association with PSC are currently lacking
AIH	Level 3	A case-control study reports a slightly increased AIH risk among smokers compared with never-smokers[25]	Level 3	Mechanistic evidence linking smoking to AIH pathogenesis remains scarce
Liver transplantation	Level 3	Observational studies report worse long-term post-transplant outcomes despite minimal effects on early complications[26,27]	Level 2	Immunological and experimental studies indicate that cigarette smoke modulates innate and adaptive immune responses and may interfere with pathways involved in transplant tolerance, potentially promoting alloimmune activation[28]
Advanced fibrosis and cirrhosis	Level 1	Large observational studies report a higher risk of advanced fibrosis, particularly with ≥ 10 pack-years and in MASLD or chronically elevated alanine aminotransferase[29,30]	Level 1	Animal and in vitro studies indicate HSC activation through oxidative and inflammatory stress, amplified TGF-β/Smad collagen synthesis, and sustained NF-κB signaling[2]
HCC	Level 1	Meta-analyses of observational studies report increased HCC incidence and mortality, especially among current and heavy smokers[31,32]	Level 1	Animal and in vitro studies indicate NF-κB/MAPK-driven proliferation, apoptosis escape, TGF-β and Wnt/β-catenin-mediated EMT/invasiveness, and angiogenic activation[2]

Clinical and mechanistic evidence was graded as level 1 (high), level 2 (moderate), or level 3 (limited), based on study design, sample size, consistency, and completeness of mechanistic pathways. HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; ROS: Reactive oxygen species; IL-33: Interleukin-33; Treg: Regulatory T cell; HCV: Hepatitis C virus; MR: Mendelian randomization; MASLD: Metabolic-associated steatotic liver disease; ALD: Alcohol-related liver disease; ER: Endoplasmic reticulum; PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; AIH: Autoimmune hepatitis; HSC: Hepatic stellate cell; TGF-β: Transforming growth factor-β; NF-κB: Nuclear factor kappa B; MAPK: Mitogen-activated protein kinase; EMT: Epithelial-mesenchymal transition.

Table 2 Major toxic constituents of tobacco smoke and their established mechanisms of hepatic injury

Toxic component	General pathogenic mechanism	Specific hepatotoxicity mechanism	Ref.
Polycyclic aromatic hydrocarbons	Aryl hydrocarbon receptor activation and systemic enzyme induction; and DNA adducts	CYP1A1/1B1 mediated epoxidation; DNA adducts: Form covalent bonds with hepatic DNA, initiating mutagenesis	[35-37]
Nitrosamines	DNA alkylation	CYP2E1 mediated α-hydroxylation; DNA alkylation: Potent alkylating agents covalently modify DNA, initiating mutagenesis	[38]
Acrolein	Protein adduction and oxidative damages	Glutathione depletion: An electrophile that rapidly depletes hepatic glutathione, impairing detoxification; mitochondrial toxicity: Disrupts mitochondrial function in hepatocytes	[39-41]
Benzene	Chromosome aberrations; oxidative stress and apoptosis; aberrant DNA repair mechanisms and epigenetic alterations	CYP2E1 mediated oxidation; cytotoxicity: Causes oxidative damage and necrosis in liver cells	[42-44]
Cadmium	Oxidative stress	Accumulation: Long-term accumulation in the liver (half-life: 25-30 years); inflammation: Inhibits antioxidant enzymes and induces chronic inflammation	[45]
Nicotine	Highly addictive	Lipid metabolism: Dysregulates hepatic lipid metabolism, promoting steatosis; fibrosis: Accelerates liver fibrogenesis via oxidative stress pathways	[46,47]
Free radicals	Macromolecule oxidation	Lipid peroxidation: Directly damages hepatocyte membranes via lipid peroxidation; Kupffer cell activation: Triggers immune response in the liver	[4,48]
Carbon monoxide	Competitive binding to hemoglobin	Hypoxia: Causes hypoxic injury to hepatocytes by reducing oxygen delivery	[49,50]

CYP2E1: Cytochrome P450 2E1.