Noncovalent interactions as key modulators of PFAS translocation, lipid-protein affinity, and tissue partitioning.

Per- and polyfluoroalkyl substances (PFAS) are synthetic compounds that persist in the environment due to their metabolic degradation. Despite growing evidence of complex transport mechanisms, critical gaps remain in understanding membrane transport, tissue distribution, multimodal uptake pathways, and predictive models that fail to capture emerging PFAS or organ-specific kinetics. This review examines how the structure of PFAS drives persistence and facilitates membrane transport through noncovalent interactions and intrinsic molecular properties. Evidence from toxicokinetic studies and membrane biophysics indicates that amphiphilic PFAS disrupt lipid packing and utilize multiple uptake routes, including passive diffusion, carrier-mediated transport, endocytosis, and nanoparticle-assisted uptake. Transport kinetics and efficiency depend on organ-specific physiology, transporter expression profiles, and the lipid-protein composition of membranes, as well as on PFAS structure (e.g., chain length, headgroup chemistry, hydrophobic-hydrophilic balance). Transport efficiency depends on organ physiology, transporter expression, and membrane composition, as well as PFAS characteristics such as chain length and headgroup chemistry. Noncovalent interactions govern partitioning and retention in high-burden tissues such as liver, kidneys, brain, and placenta, with short-chain PFAS favoring passive diffusion and long-chain PFAS relying on carrier-mediated and endocytic pathways. Essential data gaps were addressed, and research needs were identified to advance mechanistic understanding and improve predictive modeling of PFAS behavior.