Membrane-Targeted Consequences of Acetaminophen Toxicity and Off-Target Effects of Antimicrobial Peptides on Host...

Acetaminophen (paracetamol, APAP) is a widely used analgesic and antipyretic drug. Under normal physiological conditions, it does not directly interact with or disrupt cellular membranes. However, in cases of acetaminophen overdose or toxicity, severe cellular damage has been described, involving a broad spectrum of effects at different cellular levels. These toxic effects may involve membrane structures, including mitochondrial, plasma, and other intracellular membranes. Antimicrobial peptides (AMPs) are short, usually cationic and amphipathic peptides produced by both microorganisms and multicellular organisms, serving diverse defensive and competitive functions. In many cases, they exert their antimicrobial activity by direct interaction with bacterial or fungal membranes, leading to membrane destabilization and cell death. Owing to this membrane-targeting mechanism, AMPs may also interact with eukaryotic cell membranes, thereby exerting toxic or off-target effects under certain conditions. Here, we review the current knowledge on the membrane-related effects of acetaminophen toxicity and the mechanisms by which AMPs interact with biological membranes. In the event of combined exposure to acetaminophen and AMPs in therapeutic or experimental settings, the biological consequences remain unexplored. Such combined exposure may give rise to toxic effects and membrane-associated alterations. We further discuss potential mechanisms of interference, additive toxicity, and synergistic interactions between acetaminophen and AMPs, highlighting critical knowledge gaps and directions for future research.