Cigarette smoke exposure worsens the severity of alcoholic liver disease by increasing CYP pathway signaling in mice

Cigarette smoke (CS) is a major risk factor for both acute and chronic diseases, predominantly impacting the lungs and cardiovascular system. Increasing evidence indicates that CS also has substantial but underappreciated effects on liver health, including accelerating the progression of alcoholic liver disease (ALD). Because smoking and alcohol consumption often co-occur in clinical populations, understanding their combined effects is important for translational research. This study aimed to elucidate the mechanisms by which CS intensifies ALD through a comprehensive assessment of histopathological changes, biochemical indices, and molecular alterations in the liver. Six-week-old male C57BL/6 mice were initially exposed to three concentrations of CS (150, 300, and 600 μg/L) or filtered air for 2 h per day, 5 days each week, and then administered ethanol to induce ALD. Exposure to CS markedly worsened alcohol-induced liver injury, as evidenced by higher serum alanine aminotransferase and aspartate transaminase activities, increased hepatic lipid accumulation, enhanced oxidative stress, and elevated inflammation. Mice subjected to both CS and ethanol displayed more pronounced hepatic injury than those exposed to either stimulus alone, suggesting an additive deleterious effect that accelerates ALD progression. Importantly, CS strongly induced hepatic cytochrome P450 enzymes, particularly CYP1A2 and CYP2E1, thereby enhancing ethanol metabolism and worsening ALD progression. This mechanistic effect provides an insight that contributes a notable element of novelty to the study. Confirmatory results were observed in ex vivo studies, where primary hepatocytes treated with various concentrations of CS extract and 100 mM ethanol showed comparable injury patterns and CYP induction. Overall, these results indicate that CS exposure exacerbates ALD development, partially through the modulation of hepatic cytochrome P450 enzyme activity.