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.

Keywords: 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.