Forever Chemicals, Finite Defenses: PFAS Burden the Liver, Break Mitochondria, and Outpace Modern Regulation.

Per- and polyfluoroalkyl substances (PFAS) continue to be one of the most persistent global contaminants and are increasingly recognized as leading metabolic- and hepatic-dysfunction mediators. Despite extensive investigation of PFAS toxicity, a critical gap in the identification and integration of toxicokinetic drivers of hepatic bioaccumulation with mechanistic pathways driving mitochondrial and nuclear receptor-related injury, more specifically, with respect to alternative PFAS strategies, still remains. Legacy PFAS, including PFOA and PFOS, accumulate in the liver and disturb mitochondrial homeostasis as they disrupt β-oxidation, induce oxidative stress, and alter lipid and bile acid metabolism. Meanwhile, the next-generation PFAS variants (including short-chain and polymeric substitutes) are rapidly increasing in environmental concentrations, but remain insufficiently characterized and poorly regulated, raising concerns that substitution-based strategies may maintain their toxicological risk. We summarize the evidence of the association between PFAS bioaccumulation and mitochondrial dysfunction, metabolic reprogramming, and inflammatory signaling, and illustrate mechanistic convergence across legacy and emerging PFAS. We also review insights from recent experimental models, such as 3D hepatocyte systems and human-relevant receptor platforms that more closely mimic chronic exposure states. This review emphasizes mechanistic convergence across legacy and emerging PFAS, highlighting shared pathways that may persist despite chemical substitution. Thus, we discuss key gaps in monitoring, toxicity assessment, and policy, including the requirement of regulatory paradigms that treat PFAS as a class rather than individual compounds.