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

Abstract

Cigarette smoking is a major yet often underappreciated contributor to liver injury across a broad spectrum of liver diseases. Beyond its well-known systemic toxicity, accumulating evidence demonstrates that tobacco exposure induces hepatocellular damage through excessive oxidative stress, mitochondrial dysfunction, chronic inflammation, immune dysregulation, and genotoxicity. These processes not only initiate liver injury but also synergize with key hepatic risk factors - including hepatitis B virus and hepatitis C virus infections, metabolic dysfunction, and alcohol use - to accelerate progression from steatosis and steatohepatitis to fibrosis, cirrhosis, and hepatocellular carcinoma. Epidemiologic studies, large national cohort studies, and Mendelian randomization analyses identify smoking as an independent and dose-dependent risk factor for metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, viral hepatitis-related complications, advanced fibrosis, liver cancer, and adverse posttransplant outcomes. Despite variability in the strength of evidence across different liver diseases, smoking remains insufficiently recognized in routine hepatology practice, and its hepatic consequences are frequently overshadowed by other risk factors. Integrating standardized smoking assessment and cessation interventions into liver disease management may substantially reduce disease progression and liver-related mortality. Meanwhile, important knowledge gaps persist regarding the histologic reversibility of smoking-related injury, the long-term legacy effects of smoking, and the hepatic toxicity of emerging products such as e-cigarettes. Addressing these gaps is essential for developing evidence-based clinical strategies and public health policies.

Key Words: Smoking; Hepatic disease; Liver injury; Chronic liver disease progression; Smoking cessation

Core Tip: Cigarette smoking is an underrecognized yet independent risk factor across the spectrum of liver diseases. This review synthesizes mechanistic, epidemiologic, and genetic evidence demonstrating that smoking induces hepatocellular injury through oxidative stress, mitochondrial dysfunction, inflammation, immune dysregulation, and genotoxicity, while synergizing with viral hepatitis, metabolic dysfunction-associated steatotic liver disease, alcohol use, and other hepatic risk factors to accelerate disease progression. We also highlight the clinical implications of smoking assessment and cessation in hepatology practice and identify key knowledge gaps regarding reversibility, legacy effects, and emerging tobacco products.

INTRODUCTION

Cigarette smoking remains a major preventable cause of global morbidity and mortality. Although clinical practice in hepatology continues to prioritize conventional risk factors such as alcohol use and metabolic syndrome, accumulating evidence indicates that smoking is independently associated with the incidence, severity, and clinical outcomes of multiple liver diseases - an association that remains insufficiently recognized in both public health discourse and routine clinical care[1]. The scale of this issue is reflected in epidemiologic observations: Approximately 40% of patients with liver disease have a history of smoking[2], and this proportion increases to 60% among individuals with alcohol-related liver disease (ALD)[3]. Despite these data, the contribution of cigarette smoking to liver pathology is frequently underestimated, raising concern that the burden attributable to smoking may continue to increase.

The biological mechanisms underlying this clinical association further underscore the hepatotoxic potential of tobacco exposure. As the principal organ responsible for xenobiotic metabolism, the liver is highly susceptible to tobacco-derived toxicants, which induce oxidative stress, mitochondrial dysfunction, proinflammatory signaling, and genotoxic injury[1]. Nicotine has been shown to activate hepatic stellate cells (HSCs), thereby promoting fibrogenesis, while concomitant exposure to additional hepatic insults - such as alcohol consumption, metabolic dysfunction, or viral hepatitis - exerts a synergistic “multiple-hit” effect that accelerates disease progression[4-9]. Furthermore, numerous tobacco derivatives undergo metabolic activation in the liver to form DNA-damaging intermediates, thereby contributing to hepatocarcinogenesis[10]. Compounding these risks, emerging evidence suggests a potential legacy effect of long-term smoking, whereby persistent structural and molecular alterations may not fully resolve after cessation.

In light of these concerns, there is an urgent need to update the current understanding by providing a critical synthesis of the available evidence. The current literature is characterized by heterogeneous study designs, diverse diagnostic criteria, and varying population backgrounds, which complicate the consolidation of clear clinical messages. Furthermore, as the epidemiology of liver disease continues to evolve, the interplay between smoking and other risk factors requires systematic investigation. A summary of current clinical and mechanistic evidence across major liver diseases is presented in Table 1[2,7,11-32].

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.

To address these gaps, this narrative review aims to provide a comprehensive synthesis of epidemiologic, clinical, and mechanistic data regarding smoking and liver health. A narrative review format was adopted to synthesize findings across hepatology, toxicology, and epidemiology, thereby enabling the development of a coherent framework for smoking-related liver injury and a critical evaluation of research gaps, with emphasis on large cohort studies, meta-analyses, Mendelian randomization (MR) studies, and key mechanistic investigations. This review will delineate the pathophysiological pathways through which tobacco constituents exacerbate liver injury, assess the impact of smoking across the spectrum of liver diseases - from pre-cirrhotic stages to cirrhosis and hepatocellular carcinoma (HCC) - and examine its interactions with major hepatotoxic factors, including hepatitis B virus (HBV), hepatitis C virus (HCV), and metabolic comorbidities. Finally, it will discuss translational implications for clinical practice and public health policy and identify pressing research priorities to guide future intervention strategies. By integrating multidisciplinary evidence, this review seeks to clarify the true magnitude of smoking-associated hepatotoxicity and to support the development of targeted, evidence-based prevention efforts.

A comprehensive literature search was conducted in PubMed and Web of Science to identify relevant articles published up to November 2025. Priority was given to large prospective cohort studies, systematic reviews and meta-analyses, and MR studies to assess causal relationships. Mechanistic studies - including in vitro experiments and animal models - were also included to elucidate the underlying biological pathways. The evidence was synthesized narratively, with emphasis on dose-response relationships, consistency across study designs, and interactions with major hepatotoxic factors.

BIOLOGICAL BASIS OF SMOKING-INDUCED LIVER INJURY

Harmful components of tobacco

Tobacco smoke is a complex aerosol containing thousands of chemical compounds that pose significant health risks[33,34]. Table 2 presents a mechanism-based classification of the principal hepatotoxic components[4,35-50]. These compounds converge on oxidative stress, inflammatory signaling, and mitochondrial dysfunction, thereby providing a mechanistic basis for smoking-related liver injury.

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.

Core mechanisms

Tobacco exposure initiates a series of interconnected pathological processes in the liver. These processes begin with excessive oxidative stress and metabolic toxicity, progress through sustained inflammation and impaired immune surveillance, and ultimately converge on genomic instability and malignant transformation. These biological alterations constitute a common pathogenic framework through which smoking accelerates the onset and progression of liver injury, regardless of the underlying etiology.

Oxidative stress and lipid peroxidation: Tobacco smoke introduces a substantial number of oxidants into the bloodstream, which reach the liver, deplete antioxidant defenses, and amplify reactive oxygen species (ROS) production[4,51,52]. A central contributor to this oxidative burden is the induction of cytochrome P450 enzymes - particularly cytochrome P450 2E1 - which generate ROS during xenobiotic metabolism via uncoupled electron transfer[53]. This oxidative surge induces lipid peroxidation in hepatocyte membranes, leading to the formation of cytotoxic aldehydes such as 4-hydroxynonenal and malondialdehyde[54,55]. These lipid-derived electrophiles propagate membrane damage, impair mitochondrial and endoplasmic reticulum (ER) integrity, and promote hepatocyte dysfunction and cell death[56,57]. Oxidative stress represents one of the earliest detectable events in tobacco-induced liver injury, thereby establishing the molecular context for subsequent inflammation, fibrosis, and carcinogenesis.

Organellar dysfunction - mitochondrial failure and ER stress: Tobacco-driven oxidative stress rapidly overwhelms mitochondrial and ER homeostasis[58]. Cigarette smoke reduces mitochondrial respiration and membrane potential, disrupts cristae architecture, and induces damage to mitochondrial DNA and electron transport chain components, collectively decreasing β-oxidation efficiency and increasing electron leak-derived ROS generation[10]. These defects establish a self-reinforcing cycle of mitochondrial dysfunction and oxidative injury.

Concurrently, reactive aldehydes such as acrolein and 4-hydroxynonenal impose substantial ER protein-folding stress, thereby activating the unfolded protein response[59]. Although early unfolded protein response signaling is adaptive, persistent activation results in the upregulation of binding immunoglobulin protein and marked induction of C/EBP homologous protein, a proapoptotic effector that orchestrates hepatocyte death under unresolved ER stress[60,61]. ER stress further disrupts lipid synthesis, folding, and secretion pathways and enhances inflammatory signaling through inositol requiring enzyme-1α- and protein kinase-like ER kinase-dependent cascades[62]. Mitochondrial failure and ER stress integrate oxidative, metabolic, and inflammatory insults, thereby lowering hepatocyte resilience and contributing to the progression of liver disease.

Chronic inflammation: Persistent oxidative injury induces damaged hepatocytes to release damage-associated molecular patterns, such as high-mobility group box 1, adenosine triphosphate, and mitochondrial DNA[63,64]. These signals activate Kupffer cells and infiltrating macrophages, promoting a shift toward a proinflammatory phenotype[65]. This inflammatory response accelerates hepatocyte death, recruits additional immune cells, and sustains chronic hepatic inflammation, thereby fostering fibrogenesis[66-68].

Immune suppression and immune escape: Despite provoking inflammation, cigarette smoke simultaneously impairs adaptive immunity[69,70]. Nicotine and polycyclic aromatic hydrocarbons suppress dendritic cell maturation, inhibit T-cell activation and proliferation, and diminish cytotoxic function[71-73]. Reduced antiviral and antitumor immune surveillance permits injured, infected, or genetically altered hepatocytes to persist rather than being cleared[11,74]. This immune dysfunction not only permits ongoing hepatic injury but also lowers the threshold for clonal expansion of mutated cells and promotes escape from immune-mediated elimination[75,76]. Thus, tobacco exposure creates a state of “inflamed immunosuppression”, amplifying liver injury while reducing immune surveillance.

Genetic toxicity and carcinogenesis: Many tobacco-derived compounds - particularly polycyclic aromatic hydrocarbons and nitrosamines - require metabolic activation in the liver to form highly reactive electrophilic intermediates[35]. These intermediates form DNA adducts, induce base modifications, and cause DNA strand breaks[5,77,78]. Oxidative stress further exacerbates DNA damage and compromises DNA repair mechanisms[79]. Over time, the accumulation of oncogenic mutations and loss-of-function alterations in tumor suppressor genes destabilize hepatocyte homeostasis and predispose hepatic tissue to malignant transformation[80,81]. Genotoxic stress therefore represents a culminating step in smoking-related hepatocellular injury, linking chronic injury to carcinogenic progression.

INDEPENDENT AND INTERACTIVE ETIOLOGIC EFFECTS

Clinical and experimental evidence consistently demonstrates that tobacco exposure induces measurable liver injury even in the absence of specific liver diseases. In young adult males who smoked more than 20 cigarettes per day for over one month, serum alanine aminotransferase and aspartate aminotransferase levels were significantly higher than those in nonsmokers, accompanied by elevations in alkaline phosphatase and total bilirubin (mean differences of 16.3 IU/L and 0.392 mg/dL, respectively)[82,83]. These changes reflect early hepatocellular injury with mild cholestatic stress. Population-based data further indicate that lighter or intermittent smokers exhibit smaller or nonsignificant biochemical alterations, supporting a clear dose-response relationship. Experimental studies in albino rats confirm direct hepatocellular toxicity, with liver injury markers increasing during tobacco exposure and normalizing after cessation[84]. Collectively, these findings indicate that smoking imposes a baseline hepatic burden, thereby lowering the threshold for injury in disease-specific contexts. The overall strength of the clinical and mechanistic evidence is summarized in Table 1. Supplementary Table 1 summarizes the study characteristics of all included studies that examined the association between smoking and liver-related outcomes.

Viral hepatitis (HBV/HCV)

Smoking adversely affects the host antiviral immune response, thereby potentially altering the clinical course of viral hepatitis. Longitudinal evidence indicates that smokers have a significantly lower likelihood of achieving hepatitis B surface antigen seroclearance than nonsmokers, suggesting that smoking may hinder the functional cure of HBV infection. Mechanistically, smoking modulates antiviral immunity by upregulating immune checkpoint molecules. Studies demonstrate that smokers with HBV infection exhibit significantly elevated programmed cell death protein 1 expression on peripheral CD4+ and CD8+ T cells, as well as on CD20+ B cells, with expression levels positively correlating with cumulative smoking exposure[85]. These findings indicate a dose-dependent induction of an immunosuppressive state. Furthermore, this immunosuppression appears partially reversible; in vitro depletion of regulatory T cells restores HBV-specific T-cell function more substantially in samples obtained from smokers than in those from nonsmokers[86]. Collectively, these findings suggest that smoking impairs HBV clearance by fostering an immunosuppressive microenvironment characterized by programmed cell death protein 1 upregulation and enhanced regulatory T cell activity. Therefore, therapeutic strategies targeting these immune checkpoints may hold particular promise for patients with chronic HBV infection who smoke[87].

Epidemiologic data from the United States National Health and Nutrition Examination Survey reveal a marked contrast in smoking behavior among individuals with HCV infection. The prevalence of smoking among HCV-positive individuals is substantially higher at 62.4%, nearly triple the 22.9% observed among HCV-negative counterparts, with no significant sex-based difference. Furthermore, smoking behavior is more severe in the HCV-positive population, characterized by a higher likelihood of daily smoking and a greater clustering of adverse psychosocial factors, including depression, substance use, and economic hardship. These complex barriers contribute to a lower smoking cessation rate among HCV-positive individuals than among the general population. Importantly, the coexistence of smoking and HCV infection represents a substantial compounding health risk, as both are independent risk factors for HCC, chronic obstructive pulmonary disease, cardiovascular disease, diabetes mellitus, and chronic kidney disease, thereby leading to a significantly amplified disease burden[12,88,89].

Multiple studies have demonstrated that HBV and HCV infections, together with cigarette smoking, exert significant synergistic effects on the development of severe liver disease, particularly HCC. In a recent systematic review and meta-analysis, Shadi et al[90] reported that HBV/HCV coinfection increases the risk of HCC by more than 30-fold and that the combined effects of HBV or HCV infection with cigarette smoking increase the risk by approximately 20-fold and 25-fold, respectively. These amplified risks may be explained by multiple overlapping mechanisms, including smoking-induced oxidative stress, DNA adduct formation, immune suppression, and the chronic inflammatory and regenerative stress associated with viral hepatitis[12,91,92]. Collectively, these processes create a highly procarcinogenic hepatic microenvironment that accelerates progression from chronic hepatitis to cirrhosis and ultimately to HCC.

From a population-level perspective, the high prevalence of smoking among individuals with viral hepatitis further magnifies its contribution to the overall disease burden. Sherman and Llovet[93] emphasized that although the individual relative risk associated with smoking is modest, its high prevalence results in a population-attributable fraction for HCC approaching 50%, exceeding that of HBV or HCV infection alone. In regions where HBV and HCV are endemic, this overlap in exposures indicates that a substantial proportion of patients face compounded risks arising from both viral infection and tobacco use. Therefore, the concurrent implementation of antiviral therapy and structured smoking cessation interventions in the management of chronic hepatitis may represent a crucial strategy for reducing the incidence of advanced liver disease and HCC[93].

Metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty liver disease (FLD), encompasses a spectrum ranging from simple steatosis to steatohepatitis (metabolic dysfunction-associated steatohepatitis, formerly nonalcoholic steatohepatitis), fibrosis, and cirrhosis. This entity emphasizes underlying metabolic dysfunction - such as obesity, insulin resistance, and metabolic syndrome - which constitutes the principal driver of disease development and progression.

Evidence from cohort studies and meta-analyses: The prevalence of MASLD increased from 10.6% in 1990 to 16.1% in 2021, demonstrating a sustained and rapid upward trend[94]. A meta-analysis of 20 cohort studies published between 2010 and 2023 demonstrated a significant association between smoking and the risk of FLD, with a pooled odds ratio (OR) of 1.14 [95% confidence interval (CI): 1.05-1.24][95]. Subgroup analyses revealed that this association was particularly significant in prospective cohort studies, whereas it did not reach statistical significance in cohort-based cross-sectional studies. Notably, sex-stratified analyses in Asian populations indicated a significantly increased risk of FLD among male smokers, whereas no significant association was observed among females[96].

This observation is further supported by data from the 2019-2020 Korea National Health and Nutrition Examination Survey. Using the MASLD liver fat score for diagnosis, the analysis demonstrated a significant positive association between current smoking status and an increased risk of MASLD, with a clear dose-response relationship. The risk was notably higher in males than in females. Importantly, an elevated risk persisted among former smokers who had quit for fewer than 10 years. Furthermore, a pronounced dose-dependent relationship was observed between cumulative smoking exposure and the likelihood of developing MASLD, with risk increasing in parallel with greater pack-year exposure[96].

Collectively, these findings indicate that smoking is an important risk factor for the development of FLD, with effects demonstrating dose dependency and a potentially prolonged risk reduction period following cessation. In addition to established risk factors for FLD, clinicians should incorporate smoking cessation counseling into comprehensive management strategies for patients with FLD.

Smoking-induced mechanisms driving MASLD progression: Nicotine impairs insulin signaling, thereby promoting systemic insulin resistance and increasing hepatic delivery of free fatty acids[97,98]. In parallel, smoke exposure suppresses hepatic AMP-activated protein kinase activity, reducing β-oxidation and removing the inhibitory constraint on sterol regulatory element-binding protein 1c (SREBP-1c)-driven lipogenesis[99]. These mechanisms drive the liver toward a steatotic state, impair lipid disposal, and increase the risk of progression from steatosis to steatohepatitis[100,101].

ALD

Epidemiologic evidence: A nationwide Korean cohort study demonstrated that smoking acts as a significant risk multiplier among individuals who consume alcohol, increasing the incidence of ALD, ALD-related cirrhosis, and HCC by 1.32-fold, 1.53-fold, and 1.53-fold, respectively (all P < 0.001)[102]. Furthermore, a pronounced sex disparity was observed: Women with high-risk alcohol consumption who smoke faced a substantially higher risk of ALD, cirrhosis, and HCC than their male counterparts, with risk ratios of 6.08 vs 4.40 for ALD[102]. Mechanistically, smoking and alcohol synergistically accelerate liver disease progression through shared pathways, including oxidative stress, free radical-mediated injury, inflammation, and insulin resistance, collectively driving progression from fatty liver to fibrosis, cirrhosis, and HCC[106]. Consequently, smoking not only increases the incidence of ALD but also worsens its clinical course, leading to higher rates of post-liver transplant complications and increased mortality.

Mechanistic synergy - oxidative stress, acetaldehyde, and impaired regeneration: Cigarette smoking exacerbates ALD through the convergence of oxidative, metabolic, and regenerative insults[21]. Tobacco-induced upregulation of cytochrome P450 2E1 intensifies alcohol-driven ROS production and lipid peroxidation, thereby amplifying hepatocellular injury beyond that observed with either exposure alone[53]. In parallel, alcohol-stimulated SREBP-1-dependent lipogenesis and impaired mitochondrial β-oxidation promote hepatic fat accumulation, while smoking further increases lipotoxic burden and accelerates progression from steatosis to steatohepatitis[103,104]. Nicotine-triggered ROS-hydroxynonenal-p21 signaling additionally suppresses hepatocyte proliferation, thereby weakening regenerative capacity and permitting cumulative injury[105].

In the context of alcohol-induced hepatitis, tobacco exposure aggravates hepatic inflammation through activation of the nuclear factor kappa B (NF-κB) pathway[106]. Components such as nicotine-derived nitrosamine ketone in cigarette smoke impair insulin-like growth factor signaling, while oxidative stress derived from both alcohol and smoking activates inflammatory cascades that enhance hepatocellular injury and necrosis[107,108]. This synergistic metabolic, inflammatory, and regenerative dysfunction increases susceptibility to fibrosis.

Autoimmune liver diseases

A large population-based case-control study from the United Kingdom provides important evidence linking smoking to an increased risk of autoimmune hepatitis (AIH). The analysis found that individuals with a history of smoking had a significantly higher risk of AIH than never-smokers (adjusted OR = 1.20, 95%CI: 1.03-1.40), based on 987 cases and 6767 matched controls. The model was adjusted for matching factors (sex, 20-year age categories, general practice, and calendar year of registration), as well as continuous age and socioeconomic status, measured using the Index of Multiple Deprivation quintiles[25]. This association was more pronounced in women and was particularly elevated among middle-aged individuals (40-59 years). Mechanistically, tobacco smoke may trigger autoimmune responses in susceptible individuals through pathways involving oxidative damage and immune dysregulation[109]. These findings indicate that smoking constitutes a significant environmental risk factor for AIH development, with a potentially stronger effect observed in women and middle-aged populations[25].

Regarding primary biliary cholangitis (PBC), smoking has been associated with both disease development and progression. A meta-analysis found that smoking significantly increases the risk of advanced liver fibrosis in patients with established PBC (pooled OR = 3.00, 95%CI: 1.18-7.65), based on 544 patients with PBC[23]. Furthermore, a systematic review demonstrated that individuals who had ever smoked had a higher risk of developing PBC than nonsmokers (pooled OR = 1.31, 95%CI: 1.03-1.67; I² = 89%), based on 4131 patients with PBC and 4351 participants without PBC[22]. This association was also observed in pregnant patients with PBC, who showed a greater likelihood of having a history of smoking[110]. Collectively, these findings strengthen the evidence linking smoking to adverse outcomes in autoimmune cholestatic liver disease. In contrast to its role in most other liver conditions, smoking exhibits a distinct inverse association with the risk of primary sclerosing cholangitis (PSC). Meta-analytic data demonstrate that both current smokers (pooled OR = 0.31, 95%CI: 0.18-0.53, based on 2307393 participants) and former smokers (pooled OR = 0.52, 95%CI: 0.44-0.61, based on 2307393 participants) have a significantly lower risk of developing PSC than never-smokers[24]. This opposing association suggests that, despite certain overlapping clinical features, the underlying pathogenic mechanisms of PBC and PSC likely differ substantially.

SMOKING IN ADVANCED LIVER DISEASE

Fibrosis and cirrhosis

Evidence from cohort studies and MR: An MR analysis using European genome-wide association study data provides evidence supporting a causal relationship between smoking and progression of liver fibrosis. The study demonstrated that a history of smoking was significantly associated with an increased risk of liver fibrosis and cirrhosis. Notably, previous smoking status showed a particularly strong association with disease risk, whereas never-smoking status was inversely associated with the outcome. Six smoking-related exposures were evaluated, including ever smoking, pack-years of smoking, age at smoking initiation, never smoking, current smoking, and former smoking. Previous smoking status was defined as participants who had smoked previously but had recently quit completely. MR-Egger regression indicated no evidence of horizontal pleiotropy (P > 0.05), and the weighted median estimate supported the robustness of the findings [OR = 168.202, 95%CI: (5.980-4.730 × 10³)]. Sensitivity analyses further confirmed the absence of substantial genetic confounding, strengthening the inference of causality[111]. A large prospective cohort study conducted in China, involving 500000 adults with a median follow-up of 10 years, further demonstrated that current regular smoking was associated with a 28% increased risk of chronic liver disease (CLD) mortality. Notably, this study identified a synergistic interaction between smoking and solid fuel use: Individuals with combined long-term solid fuel use for cooking and regular smoking had the highest risk of CLD mortality [hazard ratio (HR) = 1.71, 95%CI: 1.32-2.20], based on 350349 participants and adjusted for education, household income, alcohol consumption, long-term heating fuel exposure, cooking stove ventilation, body mass index, prevalent diabetes, hepatitis B surface antigen status, and recall period duration. The protective effect of smoking cessation was evident, as former smokers who had quit for a median of 10 years experienced a substantial reduction in excess risk of CLD mortality; some studies suggest that this risk may approach that of never-regular smokers[112].

Fibrogenic pathways

HSC activation: In the healthy liver, HSCs remain quiescent and function primarily as vitamin A-storing cells within the space of Disse[113]. Smoking disrupts this quiescent state through several converging stimuli, including oxidative stress products, inflammatory cytokines released by Kupffer cells, and apoptotic debris derived from injured hepatocytes[114,115]. Once activated, HSCs transdifferentiate into extracellular matrix-producing myofibroblasts and secrete collagen types I and III, as well as fibronectin, progressively distorting sinusoidal architecture[116-118].

Nicotine, acting through nicotinic acetylcholine receptors expressed on HSCs, promotes HSC proliferation and collagen type I expression, thereby further driving fibrosis progression[119]. Additionally, lipopolysaccharide derived from gut bacteria activates Toll-like receptor 4 on HSCs, thereby enhancing HSC activation and collagen deposition and exacerbating liver fibrosis[120]. Thus, HSC activation represents a final common pathway through which smoking-related cellular injury becomes established as fibrotic tissue.

Transforming growth factor-β/Smad signaling: Transforming growth factor-β (TGF-β) is a central molecular driver of hepatic fibrogenesis[6]. Tobacco exposure enhances TGF-β expression through oxidative and inflammatory stimuli, thereby lowering the threshold for fibrotic activation[119]. Upon activation, TGF-β engages the TβRII-TβRI/ALK5 receptor complex, triggering Smad2/3 phosphorylation and Smad-dependent transcription of collagen genes (such as COL1A1 and COL1A2), plasminogen activator inhibitor-1, and additional extracellular matrix-promoting targets[121-124]. This process simultaneously enhances matrix synthesis and suppresses matrix degradation, thereby shifting the hepatic microenvironment toward progressive fibrosis.

NF-κB inflammatory-fibrotic cascade: NF-κB serves as a central molecular link between chronic inflammation and fibrosis[107]. Tobacco smoke-derived ROS and damage-associated molecular patterns activate NF-κB signaling in Kupffer cells and hepatocytes through Toll-like receptor 4 and related pattern recognition pathways[125,126]. Activated NF-κB drives sustained transcription of proinflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-6, and IL-1β, along with chemokines that recruit monocytes and neutrophils to the hepatic microenvironment[126]. These inflammatory mediators act directly on HSCs to promote proliferation, enhance responsiveness to TGF-β, and increase collagen production[127]. NF-κB also upregulates adhesion molecules and matrix-remodeling enzymes that facilitate persistent immune-stromal crosstalk, thereby enabling fibrosis to progress from a transient injury response to chronic architectural remodeling[128].

HCC and intrahepatic cholangiocarcinoma

Cohort and pooled-analysis evidence: Smoking is an independent risk factor for both HCC and intrahepatic cholangiocarcinoma (ICC), and long-term cessation is associated with significant risk reduction. Large-scale prospective cohort studies and meta-analyses have consistently demonstrated that smoking independently increases the risk of HCC and ICC, with a clear dose-response relationship. Sustained cessation may reduce risk to a level approaching that of never-smokers. Key findings from the United States Liver Cancer Pooling Project, which included more than 1.5 million individuals from 14 cohorts, indicate that current smokers had a significantly elevated risk, with an 86% increase in HCC (HR = 1.86, 95%CI: 1.57-2.20) and a 47% increase in ICC (HR = 1.47, 95%CI: 1.07-2.02). Heavy smokers exhibited an even greater risk, reinforcing the dose-dependent association[129,130]. The benefits of cessation are substantial: Individuals who quit smoking for more than 30 years had an HCC risk nearly equivalent to that of never-smokers, and ICC risk similarly declined with prolonged abstinence[131,132]. The underlying mechanisms involve hepatic metabolic activation of tobacco carcinogens, leading to DNA damage, oxidative stress, and chronic inflammation, which collectively promote hepatocarcinogenesis[133]. These associations remain robust across diverse populations, underlying liver diseases (such as hepatitis B and MASLD), and multiple international cohorts[134,135]. Smoking avoidance has been incorporated into guidelines for liver cancer prevention and control; however, further strengthening of implementation and clinical awareness is warranted[136].

Carcinogenic pathways

Imbalance between cell proliferation and apoptosis: Tobacco smoke-induced oxidative stress and inflammatory signaling activate key prosurvival pathways, particularly NF-κB and mitogen-activated protein kinase (MAPK) signaling cascades[107,137]. NF-κB promotes cell survival by upregulating antiapoptotic genes, such as BCL2 and inhibitors of apoptosis proteins, thereby protecting transformed cells from programmed cell death[138]. Simultaneously, MAPK components - including extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 - enhance cellular proliferation and survival through regulation of transcription factors such as activator protein-1 and cAMP response element-binding protein[139-141]. Sustained activation of these pathways enables damaged or transformed hepatocytes to evade apoptosis and undergo clonal expansion, thereby laying the foundation for malignant progression.

Epithelial-mesenchymal transition and metastasis: Epithelial-mesenchymal transition (EMT) enables cancer cells to lose intercellular adhesion and acquire a mesenchymal phenotype, thereby enhancing their capacity to invade vasculature and metastasize to distant organs[142]. Tobacco smoke accelerates EMT through activation of TGF-β and Wnt/β-catenin signaling pathways[143,144]. TGF-β promotes downregulation of epithelial markers, such as E-cadherin, and upregulation of mesenchymal markers, including N-cadherin, vimentin, and fibronectin, thereby facilitating cell detachment, migration, and invasion[145]. In parallel, smoking-driven Wnt/β-catenin activation stabilizes β-catenin, promotes its nuclear translocation, and induces transcription of EMT-associated genes[146,147]. Collectively, these pathways reprogram HCC cells toward a more invasive phenotype and facilitate metastatic dissemination.

Angiogenesis: Angiogenesis - the formation of new blood vessels - is essential for tumor growth and metastasis[148]. Nicotine activates endothelial nicotinic acetylcholine receptors, engaging phosphoinositide 3-kinase, c-Src, and MAPK signaling pathways to stabilize hypoxia-inducible factor-1α and induce downstream angiogenic mediators, such as vascular endothelial growth factor and angiopoietin-2[149-151]. Tobacco exposure also activates NF-κB and MAPK pathways, thereby increasing secretion of proangiogenic factors, including IL-8 and vascular endothelial growth factor[152,153]. These converging signals create a provascular microenvironment that facilitates tumor expansion and invasion[154-156].

Sex-based differences in smoking-related hepatocarcinogenesis: Sex-based biological differences influence the hepatic response to smoking, thereby affecting disease susceptibility and progression. Epidemiologic studies indicate that men generally have a higher incidence and poorer prognosis of HCC than women, partially attributable to differences in risk factors, such as viral hepatitis, alcohol use, and metabolic syndrome[157,158]. Estrogen signaling attenuates hepatic inflammation and fibrosis, thereby suppressing HCC progression, whereas androgen signaling may promote hepatocarcinogenesis[159]. Immune regulation also differs by sex: Men typically exhibit higher levels of immunosuppressive cell populations, such as tumor-associated macrophages and regulatory T cells, which contribute to more severe disease outcomes[160]. These observations underscore the need for further investigation into sex-specific mechanisms underlying smoking-related liver diseases[161].

Liver transplantation

Smoking significantly increases the risk of mortality and posttransplant complications among both liver transplant candidates and recipients, and smoking cessation has been shown to improve clinical outcomes. Prospective and retrospective studies consistently indicate that smoking is an independent risk factor for increased mortality, as well as a higher incidence of cardiovascular events, infections, and malignancies in this population, whereas cessation is associated with improved long-term survival. Key findings demonstrate that active smoking is associated with markedly reduced posttransplant survival. A United Kingdom single-center retrospective study reported a 10-year survival rate of 54% among active smokers, significantly lower than the 77% observed among nonsmokers, and identified smoking as an independent predictor of mortality (HR = 2.23, 95%CI: 1.08-4.61, P = 0.03), based on 132 patients with a mean follow-up of 8.8 years. The analysis adjusted for age at listing, sex, ethnicity, etiology of liver disease, Child-Pugh score, Model for End-Stage Liver Disease score at listing, severity of circulatory dysfunction at listing (creatinine, glomerular filtration rate, and sodium), time on the transplant waiting list, and the presence of significant comorbidities (diabetes, treated hypertension, treated dyslipidemia, and cardiovascular disease)[162]. These findings are supported by the United States prospective PVCLD2 cohort, which reported that current smokers had a 2.17-fold increased risk of death, with mortality risk increasing by 7% for every additional 5 pack-years of smoking[163]. Larger multicenter studies further confirm lower 10-year survival rates among smokers, with risk escalating in proportion to cumulative tobacco exposure[164,165]. With respect to complications, smokers face a significantly elevated risk of cardiovascular-related mortality, infection-related mortality, and higher rates of posttransplant malignancies and biliary complications[166,167].

CLINICAL IMPLICATIONS AND PUBLIC HEALTH RECOMMENDATIONS

Smoking assessment and cessation as routine components of liver disease management

Alcohol is a well-established cause of liver disease and has corresponding diagnostic classifications. In contrast, smoking - despite its higher prevalence in the general population - has not received sufficient attention in clinical hepatology. In light of the evidence discussed above, systematic assessment of smoking history - including age at initiation, daily cigarette consumption, duration of smoking, and cessation status - should be incorporated into standard liver disease management, patient education, risk stratification, and prognostic evaluation. The development of highly sensitive, cost-effective, and scalable blood-based biomarkers may substantially advance smoking-related research and public health practice. Current approaches to monitoring smoking-related biomarkers encompass multiple domains, including metabolite profiling, DNA methylation analysis, proteomics, and metabolomics. Integrative strategies combining DNA methylation signatures with artificial intelligence algorithms and conventional blood indicators may offer particularly strong translational potential[168-171]. Smoking cessation should be considered a core therapeutic intervention for all patients with liver disease, particularly high-risk groups such as those with viral hepatitis, metabolic dysfunction-associated steatotic liver disease, or a family history of liver disease. During clinical decision-making, patients should be clearly informed about the independent hepatotoxic effects of smoking and its synergistic interactions with other risk factors to enhance risk awareness and adherence to cessation strategies. Additionally, the potential impact of smoking on pharmacologic efficacy and drug metabolism should be considered when developing individualized treatment plans. For high-risk individuals with a history of heavy, long-term smoking and additional liver disease risk factors, regular enhanced surveillance - including liver function testing, imaging, and alpha-fetoprotein measurement - is essential for early detection of liver fibrosis and early-stage HCC.

Accordingly, within the clinical management framework for liver disease, we recommend implementation of systematic measures, including screening for tobacco use among high-risk populations, provision of professional smoking cessation counseling, and integration of pharmacologic and psychological support into routine care protocols. The clinician’s role in this process is pivotal. As trusted health role models - an effect illustrated by the decline in smoking prevalence among the British public following reductions in smoking among physicians in the United Kingdom - their direct advice can effectively motivate patients; studies indicate that 50%-70% of smokers express interest in quitting, and physician counseling significantly increases cessation success rates. Therefore, physicians should proactively lead cessation efforts and arrange more intensive follow-up for patients who smoke.

To translate evidence into practice, hepatology clinics should adopt a standardized workflow for smoking assessment and cessation support. First, routine screening for tobacco use should be integrated into electronic health records, including documentation of pack-years, current smoking status, and prior quit attempts. Validated frameworks, such as the “5A” model (Ask, Advise, Assess, Assist, Arrange), may guide clinician-patient interactions. Second, brief cessation counseling should be provided during clinic visits, emphasizing liver-specific benefits of quitting - including reduced risk of fibrosis progression, HCC, and posttransplant complications. Third, pharmacologic support (nicotine replacement therapy, varenicline, or bupropion) should be offered when appropriate, with careful consideration of potential drug-drug interactions in patients with advanced liver disease. Fourth, referral pathways to specialized smoking cessation services or telehealth programs should be established, particularly for patients with complex psychosocial needs. Finally, longitudinal follow-up should include reassessment of smoking status at subsequent visits and documentation of cessation outcomes in the medical record.

Implementing smoking cessation in clinical practice faces substantial barriers, particularly among patients with HCV infection. As noted in the “Viral hepatitis (HBV/HCV)”, individuals with HCV have a smoking prevalence nearly three times that of the general population (62.4% vs 22.9%), and their smoking patterns are often more intense[12,88]. This disparity is closely associated with complex psychosocial factors, including higher rates of depression, anxiety, substance use disorders, socioeconomic hardship, and social isolation[89]. These factors not only contribute to smoking initiation and persistence but also diminish motivation and capacity to quit. Furthermore, competing health priorities - such as adherence to antiviral therapy or management of comorbid conditions - may overshadow smoking cessation efforts. Stigma associated with both HCV infection and substance use may also impede open communication about smoking between patients and health care providers. Addressing these barriers requires a multidisciplinary strategy that integrates mental health support, social services, and harm reduction approaches alongside conventional cessation interventions.

To evaluate the effectiveness of smoking cessation programs in hepatology settings, both process and outcome metrics should be monitored. Process metrics include documentation rates of smoking screening in electronic health records, the proportion of smokers offered cessation counseling or pharmacotherapy, and 6-month or 12-month self-reported abstinence rates. Outcome metrics should focus on liver-related endpoints, including changes in liver biochemistry (alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase), noninvasive fibrosis markers (fibrosis-4 index and transient elastography), and, in high-risk populations, the incidence of hepatic decompensation, HCC, and liver-related mortality. In posttransplant populations, outcome measures may additionally include cardiovascular event rates, de novo malignancies, and graft survival. Ideally, these data should be collected prospectively within routine clinical care or through dedicated registries to facilitate continuous quality improvement and long-term outcome assessment.

To translate evidence into practice, we propose actionable recommendations for hepatology clinics. Smoking assessment should routinely include age at initiation, average number of cigarettes per day, cumulative pack-years, time since cessation (for former smokers), and use of emerging tobacco products, such as e-cigarettes and heated tobacco systems. For high-risk patients - including those with cirrhosis, HCC, or posttransplant status - smoking status should be reassessed at least annually. Cessation interventions should follow an evidence-based framework, including brief clinician-delivered advice during routine visits, referral to behavioral support services, and pharmacotherapy when appropriate. First-line pharmacologic options include nicotine replacement therapy, varenicline, and bupropion. In patients with advanced liver disease, varenicline and bupropion should be used with caution because of hepatic metabolism and potential neuropsychiatric adverse effects; consultation with a specialist is recommended before initiating pharmacotherapy in individuals with decompensated cirrhosis or severe hepatic impairment.

Public health actions for liver disease prevention

At the public health level, smoking cessation is recognized as an effective intervention for the prevention and control of liver disease. Primary prevention represents the first line of defense against liver injury and should prioritize tobacco control and smoking cessation among the general population and high-risk groups. In addition to direct and secondhand smoke exposure, thirdhand smoke - a mixture of residual tobacco pollutants that persist in indoor environments - can enter the body through inhalation, dermal contact, or hand-to-mouth behaviors. Experimental studies have demonstrated that thirdhand smoke exposure disrupts key hepatic metabolic pathways, including D-glutamine and D-glutamate metabolism, glycerophospholipid metabolism, and glutathione metabolism, leading to metabolic disturbances such as lipid accumulation and choline deficiency, which may adversely affect liver health[172]. Secondary prevention is essential for patients with established CLD, as prompt smoking cessation is critical to slow progression to cirrhosis and liver cancer. This requires clinicians to provide structured behavioral interventions and pharmacologic support. From a policy perspective, public health strategies should incorporate messaging that emphasizes the hepatotoxic effects of smoking within national tobacco control campaigns and implement comprehensive measures, including legislation, increased tobacco taxation, and expansion of smoke-free public areas, to foster healthier environments. In regions with a high burden of liver disease, stricter tobacco control policies may be warranted, such as higher excise taxes, advertising restrictions, expanded smoke-free zones, targeted health education initiatives, and integration of cessation services into primary health care systems. Experience from China illustrates the effectiveness of comprehensive tobacco control measures. For example, Shanghai has reported a steady decline in adult smoking prevalence to 19.4%, accompanied by a life expectancy of 84.11 years - ranking highest nationally and comparable to developed regions worldwide. These observations underscore the public health importance of fully integrating smoking cessation into liver disease prevention and management strategies to reduce the incidence and mortality of cirrhosis and liver cancer.

FUTURE RESEARCH DIRECTIONS

While smoking cessation is a cornerstone intervention for improving liver health, its specific effects and underlying mechanisms remain incompletely understood, with several controversies and evidence gaps warranting further investigation. A primary area of complexity involves the relationship between smoking cessation and the risk of MASLD. Meta-analyses indicate that former smokers have a pooled risk ratio of 1.13 (95%CI: 1.08-1.19; prediction interval: 0.92-1.39) for MASLD prevalence compared with current smokers[173]. This association persists after adjustment for multiple confounders, including body mass index, suggesting that cessation may not confer immediate protection against MASLD, partly because of post-cessation weight gain. This pattern contrasts with the well-established evidence of rapid reversal of steatosis following alcohol abstinence. More importantly, a substantial knowledge gap exists regarding histologic changes in the liver after smoking cessation. There is a near-complete absence of prospective studies using liver biopsy to quantitatively assess pre- and post-cessation changes in parameters such as collagen proportionate area or hepatic fat vacuole area. Furthermore, MR analyses support the presence of a “legacy effect”, whereby a history of smoking - particularly former smoking status - is causally associated with a markedly elevated long-term risk of liver fibrosis and cirrhosis[111]. The “legacy effect” refers to the persistence of increased disease risk in former smokers years after cessation, reflecting cumulative structural and molecular damage from prior tobacco exposure. MR studies thus support a causal relationship between previous smoking and liver fibrosis or cirrhosis, underscoring potential long-term clinical implications[111]. However, interpretation of this effect remains limited by heterogeneity in the definition of “former smoker” across studies and the possibility of residual confounding. Standardized exposure definitions are required to more accurately quantify and interpret this association.

To address these issues systematically, future research should adopt a multilevel, integrated roadmap. To strengthen causal inference, existing large-scale cohorts should be leveraged to enable standardized exposure and outcome assessment, detailed dose-response analyses, and stratified evaluations in specific subgroups, such as women and younger smokers. These efforts should be complemented by prospective cohort designs and nested case-control studies to establish temporal relationships. In the domain of causal inference, MR analyses should be expanded and replicated using more comprehensive sets of genetic instruments to validate the causal effects of smoking on liver fibrosis, cirrhosis, and HCC. For mechanistic elucidation, integrative multi-omics approaches combined with population-based studies are required to validate associations between key pathways identified in animal models (e.g., AMP-activated protein kinase-SREBP-1 and NF-κB signaling) and smoking exposure in human liver tissue or circulating biomarkers, as well as to identify potential diagnostic biomarkers and therapeutic targets. Regarding novel tobacco product assessment, systematic in vitro and in vivo toxicologic evaluations of e-cigarettes and heated tobacco products (HTPs) are essential, alongside the establishment of long-term prospective cohorts to clarify their hepatic safety profiles. In the context of clinical intervention, priority should be given to conducting randomized controlled trials in populations with MASLD, ALD, and chronic hepatitis B to evaluate the effects of intensive cessation interventions (behavioral and pharmacologic) on liver function, fibrosis progression, and clinically meaningful endpoints, such as liver cancer incidence. In addition, a critical research direction involves investigation of the core biological mechanisms underlying cessation, including the development of mechanistic biomarkers to objectively assess short-term intervention efficacy. For policy support, economic evaluations of the impact of tobacco control policies on liver disease incidence and health care costs across diverse regions are necessary to provide robust fiscal evidence for policy decision-making.

Most current studies on e-cigarettes and HTPs are limited to short-term toxicologic investigations or animal experiments, and long-term evidence regarding their hepatic safety remains scarce. Although these products may contribute to liver injury through oxidative stress, inflammation, and metabolic alterations, the available data are derived predominantly from short-duration exposure studies rather than chronic use. Future research should prioritize well-designed prospective cohort studies and targeted toxicologic evaluations to determine the long-term hepatic risks associated with e-cigarettes and HTPs. In addition, development of specific and sensitive biomarkers is necessary to monitor liver toxicity among long-term users. Until more definitive evidence becomes available, a precautionary approach is warranted, particularly for individuals with pre-existing liver disease.

For PBC and PSC, future research should prioritize elucidating the mechanisms underlying these apparently paradoxical associations with smoking. In PSC, the observed inverse association warrants particularly rigorous evaluation, as it may result from a combination of methodological and biological factors. The potential influence of confounding must be carefully considered, most notably the strong epidemiologic association between PSC and inflammatory bowel disease (IBD). Because smoking exerts complex and well-documented bidirectional effects on IBD, this relationship may partially or fully confound the apparent protective association with PSC. Selection bias also represents a significant concern, given that many PSC studies are derived from clinical cohorts that may not be representative of the broader patient population. For example, if individuals with PSC who smoke experience higher mortality from competing causes and are therefore underrepresented in study samples, this could generate a spurious inverse association. Reverse causation should likewise be considered a plausible explanation, as early symptoms of PSC may prompt patients to reduce or discontinue smoking before formal diagnosis, leading to potential misclassification as nonsmokers in postdiagnosis analyses. If the inverse association persists after accounting for these methodological artifacts, investigation of potential biological mechanisms becomes justified. These may include the effects of nicotine on intestinal barrier integrity, direct immunomodulatory actions within the liver, or indirect effects mediated through modification of coexisting IBD. To disentangle these complex relationships and advance causal inference, future studies should employ more robust designs, including MR analyses to mitigate confounding and reverse causation, large-scale prospective cohort studies of patients with IBD incorporating longitudinal smoking data to establish temporality, and in-depth mechanistic investigations using animal models and organoid systems to examine the direct effects of specific tobacco constituents on cholangiocytes, hepatic immune cells, and the gut-liver axis. Ultimately, clarifying why the same environmental exposure exerts divergent effects across different liver diseases will deepen understanding of disease-specific pathophysiology and may identify novel therapeutic targets.

CONCLUSION

The expanding body of mechanistic, epidemiologic, and clinical evidence establishes tobacco smoking as a major, yet frequently underrecognized, contributor to liver injury across the disease spectrum. Smoking not only induces hepatocellular injury through oxidative stress, mitochondrial dysfunction, chronic inflammation, and genotoxicity but also interacts synergistically with key hepatic risk factors, including HBV, HCV, metabolic dysfunction, and alcohol use. These interactions accelerate progression from steatosis to steatohepatitis, fibrosis, cirrhosis, and ultimately HCC. Evidence from prospective cohorts, large national datasets, meta-analyses, and MR analyses consistently demonstrates that smoking is an independent and dose-dependent risk factor for both pre-cirrhotic liver disease and advanced outcomes, including cirrhosis, HCC, and posttransplant mortality (Figure 1).

Figure 1 Smoking-driven liver injury across etiologies: From toxicants to fibrosis and cancer. PAHs: Polycyclic aromatic hydrocarbons; ER: Endoplasmic reticulum; UPR: Unfolded protein response; HBV: Hepatitis B virus; HCV: Hepatitis C virus; PD-1: Programmed cell death protein 1; Treg: Regulatory T cell; MASLD: Metabolic-associated steatotic liver disease; AMPK: AMP-activated protein kinase; ALD: Alcohol-related liver disease; ROS: Reactive oxygen species; AH: Aromatic hydrocarbon; NF-κB: Nuclear factor kappa B; MAPK: Mitogen-activated protein kinase; EMT: Epithelial-mesenchymal transition; TGF-β: Transforming growth factor-β; PI3K: Phosphoinositide 3-kinase; HIF-1α: Hypoxia-inducible factor-1α; VEGF: Vascular endothelial growth factor; HCC: Hepatocellular carcinoma; ICC: Intrahepatic cholangiocarcinoma.

Despite this robust evidence, smoking remains insufficiently addressed in clinical hepatology practice. Integration of standardized smoking assessment, routine cessation counseling, and targeted interventions into liver disease management - including for patients with viral hepatitis, MASLD, ALD, autoimmune liver disease, and cirrhosis - should be regarded as essential components of contemporary hepatology care. At the population level, strengthening tobacco control policies and increasing public awareness of the hepatic consequences of smoking are crucial to reducing the incidence and mortality of liver disease.

Future research should prioritize resolution of key knowledge gaps, including the longitudinal histologic impact of smoking cessation, the molecular legacy effects of prior tobacco exposure, the hepatic toxicity of emerging tobacco products, and the development of mechanistic biomarkers to monitor liver injury progression or recovery. By elevating smoking cessation to the same level of clinical priority as antiviral therapy and alcohol abstinence, health care systems - particularly in high-burden regions - may achieve meaningful reductions in the societal and clinical burden of CLD and advance long-term public health objectives.