Mechanistic insights into PFAS-induced toxicity: from lipid membrane perturbation to ion channel and transporter dysregulation.

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants associated with a wide range of adverse health outcomes, including metabolic, developmental, and neurodevelopmental disorders. Recent evidence suggests that PFAS can act as membrane-active compounds, directly interacting with lipid bilayers. Their amphiphilic properties allow incorporation into cellular membranes, altering membrane properties. These physicochemical changes can impact the structural dynamics and functional properties of membrane proteins, particularly ion channels. A growing body of research demonstrates that PFAS modulate the activity of multiple ion channel types, including voltage-gated Ca²⁺ channels, glutamate receptors, GABAA receptors, and K⁺ channels, as well as intracellular channels such as ryanodine receptors, voltage-dependent anion channels (VDACs), and mitochondrial calcium uniporters. These effects are often observed as shifts in channel gating, conductance, and voltage dependence rather than as competition at defined ligand-binding sites, a pattern compatible with membrane perturbation acting as one contributing influence alongside direct protein interactions and other lipid-mediated mechanisms. PFAS also interact with plasma membrane transporters, altering the transport of endogenous substrates while utilizing transport systems such as organic anion and bile acid transporters for their own cellular uptake, tissue distribution, and elimination. Thus, membrane transport proteins may function both as targets of PFAS toxicity and as determinants of PFAS disposition. These effects extend beyond the plasma membrane to intracellular organelles. PFAS have been associated with Ca²⁺ and iron homeostasis across the endoplasmic reticulum-mitochondrial axis, promoting mitochondrial dysfunction, reactive oxygen species generation, and activation of cell death pathways. These observations suggest that ion channel dysfunction may contribute to the link membrane perturbations to downstream cellular damage. This review integrates current evidence on PFAS-induced membrane perturbation and ion channel dysregulation and situates these mechanisms within a multiscale framework encompassing membrane biophysics, organelle signaling, and cellular toxicity. This perspective offers a mechanistic framework for PFAS toxicity and underscores the need for integrative approaches to evaluate both legacy and emerging compounds.