Synergistic toxicity in alcohol-associated liver disease and PFAS exposure

Abstract Alcohol-associated liver disease (ALD) remains a leading contributor to global morbidity and mortality. Chronic ethanol intake drives hepatocellular damage through multiple mechanisms, such as acetaldehyde-induced cytotoxicity, dysregulated lipid metabolism, oxidative stress, and inflammation. Per- and polyfluoroalkyl substances (PFAS) have emerged as major environmental contaminants, characterized by their persistence, bioaccumulation, and capacity to disrupt hepatic function. PFAS share pathogenic pathways with ALD, including interference with mitochondrial function, oxidative stress induction, and steatosis promotion via altered lipid homeostasis. As exposure to PFAS becomes increasingly widespread and the burden of ALD continues to rise, understanding their potential synergistic impact on liver function is crucial. This review synthesizes current findings on the central mechanisms of ALD pathology, summarizes the hepatotoxic effects of PFAS, and explores their converging roles in exacerbating liver injury. Key pathways of interest include shared disruption of fatty acid oxidation, additive oxidative stress, and immunomodulation. The potential for concurrent exposure in high-risk populations (such as occupational groups with elevated PFAS exposure and higher-than-average alcohol use) warrants concern, particularly given that these people often face more limited healthcare access. By identifying mechanistic convergences, this review underscores the need for targeted studies that address how common co-exposures to PFAS and alcohol may intensify liver pathology, the value of a systems biology approach for future investigations, and the importance of implementing strategies to mitigate these synergistic hazards.