From Pathogenesis to Therapy: Extracellular Vesicles Orchestrate Cellular Crosstalk in Acetaminophen Hepatotoxicity

Drug-induced liver injury (DILI) is a major cause of acute liver failure, with acetaminophen (APAP) overdose representing the leading cause of intrinsic hepatotoxicity worldwide. Although the mechanisms of APAP-induced liver injury have been extensively characterized, recent evidence highlights a critical role for extracellular vesicles (EVs) in mediating intercellular communication during hepatic stress and injury. EVs are lipid bilayer-enclosed vesicles released by hepatocytes and non-parenchymal liver cells under physiological and pathological conditions, carrying diverse bioactive cargo, including microRNAs, mRNAs, proteins, and mitochondrial components. Following APAP exposure, EV release is rapidly increased, often preceding overt hepatocellular necrosis and elevations in conventional biomarkers such as alanine aminotransferase (ALT). EVs actively contribute to the progression of liver injury by transferring stress signals that promote oxidative stress, activate c-Jun N-terminal kinase (JNK) signaling, and stimulate innate immune responses, including neutrophil recruitment and cGAS-STING-mediated inflammation. EV-associated cargo, particularly liver-specific microRNAs such as miR-122, demonstrates greater stability and diagnostic sensitivity than traditional compared serum biomarkers, supporting its utility as an early and reliable biomarker of hepatocellular injury. Beyond their diagnostic potential, EVs also exhibit therapeutic potential. Mesenchymal stromal cell-derived EVs have been shown to attenuate APAP-induced liver injury by delivering regulatory microRNAs, such as miR-186-5p, which suppresses chemokine signaling and reduces inflammatory cell infiltration. Collectively, EV function as dynamic mediators of liver injury, serving as biomarkers and intercellular communicators, while also showing potential as therapeutic agents. A better understanding of EV biology may facilitate the development of novel diagnostic and therapeutic strategies for APAP-induced liver injury.