© 2021Oxidative stress is associated with various disease pathologies including Inborn Errors of Metabolism (IEMs), among the most important causes of childhood morbidity and mortality. At least as much as oxidative stress in cells, reductive stress poses a danger to the disruption of cell homeostasis. p62/SQSTM1, protects cells from stress by activation of Nrf2/Keap1 and autophagy pathways. In this study, we tested the role of cellular stress, mitochondrial dysfunction and autophagy via Nrf2/Keap1/p62 pathway in the pathophysiology of three main groups of IEMs. Our results showed that antioxidant and oxidant capacity alone would not be sufficient to reflect the true clinical picture of these diseases. ATP, ROS and mitochondrial membrane potantial (MMP) measurements demonstrated increased cellular stress and bioenergetic imbalance in methylmalonic acidemia (MMA), indicating mild mitochondrial dysfunction. In isovaleric acidemia (IVA), no major change was detected in ATP, ROS and MMP values. Propionic acidemia (PA), mitochondrial diseases (MIT) and mucopolysaccharidosis IV (MPS IV) might point out mitohormesis to cope with chronic reductive stress. Induction of Nrf2/Keap1/p62 pathway and increased expression of HMOX1 were detected in all IEMs. LC3B-II and p62 expression results indicated an impaired autophagic flux in MIT and MPS IV and an induction of autophagic flux in MMA, PA and IVA, but also partial expression of Beclin1, enables autophagy activation, was detected in all IEMs. We conclude that individual diagnosis and treatments are of great importance in IEMs. In addition, we assume that the application of therapeutic antioxidant or preventive treatments without determining the cellular stress status in IEMs may disrupt the sensitive oxidant-antioxidant balance in the cell, leading to the potential to further disrupt the clinical picture, especially in patients with reductive stress. To the best of our knowledge, this is the first study to simultaneously relate IEMs with cellular stress, mitochondrial dysfunction, and autophagy.