Biological pathways of per- and polyfluoroalkyl substances (PFAS): A critical review of cellular and molecular toxicity mechanisms

The biological mechanisms underlying per- and polyfluoroalkyl substances (PFAS) exposure and adverse health outcomes remain poorly understood, particularly the cytotoxic effects arising from cellular- and molecular-level interactions. Although measures have been taken to phase out legacy emissions, concerns persist regarding the continued use of highly fluorinated alternatives and the widespread environmental persistence and human exposure that remain. In this critical review, we present a holistic view of how cellular- and molecular-level PFAS interactions give rise to cytotoxic effects, such as membrane perturbation, metabolic and mitochondrial stress, and dysregulated cellular signaling and transport, that culminate in cytotoxic outcomes, including cellular dysfunction, loss of viability, and organ-specific susceptibility. This framework highlights the interdependence between PFAS interactions with key biochemical targets, including transport proteins, plasma membranes, and nuclear receptors, and downstream molecular-initiating events. We further delineate the interactive pathways influencing PFAS toxicokinetics and toxicodynamics, noting patterns related to per- and polyfluoroalkyl chain length, functional headgroups, and backbone features. Moreover, this review provides a systematic, integrative analysis of how structurally diverse PFAS engage molecular targets across human cell types, linking target interactions and cellular composition with physiological processes that shape PFAS organotropism and their differential cytotoxic outcomes. The findings of this review can support prioritization of toxicological research on PFAS with high toxicity potential, understanding their biological targets, resolving inconsistencies in reported cytotoxic effects, and establishing consensus on the adverse outcome pathways of unregulated PFAS compounds.