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.