Given the pervasive detection of perfluoroalkyl substances (PFAS) in several environmental matrices and their known toxicological effects, it is imperative to investigate their impact on the physiological responses of freshwater organisms. This research is crucial for developing effective strategies to protect aquatic ecosystems by directly addressing how PFAS influences aquatic species' health and survival. In this study, we conducted a biomonitoring analysis to evaluate the effects of naturally occurring PFAS, specifically perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), on the physiology of common chub (Squalius cephalus), a freshwater fish native to the Veneto region. We measured oxidative damage in the kidney and skeletal muscle, with results showing that low PFAS contamination is sufficient to increase protein oxidation in both tissues. Conversely, even high PFAS levels did not induce lipid peroxidation in either tissue. We also examined the expression of peroxiredoxin isoform 4 (prdx4) in the kidney, finding its down-regulation with increasing PFAS pollution, which demonstrates the minor function of Prdx4 against oxidative stress. Instead, its down-regulation plays an important role in increasing lipid accumulation in the cell, creating a hydrophobic environment that limits PFAS bioaccumulation and their capacity to bind proteins, thus preserving them from further damage.