Recent years have witnessed a widespread redundancy between the cell’s most versatile antioxidant systems such as the Thioredoxin (Trx) and glutathione (GSH)/Glutaredoxin (Grx) systems. The Trx system comprising of thioredoxin (Trx), seleno-enzyme thioredoxin reductase (TrxR), and NADPH works in concerted action where Trx upon reducing the substrate, itself gets reduced by TrxR accepting electrons from NADPH, in order to maintain the catalytic cycle [1, 2]. Trx is often referred to as a lethal gene, whose genetic ablation is expensive for the cell resulting in cell death. Glutathione (GSH), being the most predominant antioxidant system in the cell with huge substrate diversity has been noted to behave as a backup within the cell in several ways, one very relevant way is by complementing the job of TrxR in its absence and preventing cellular death . These widespread redundancies and overlapping substrates between Trx and GSH help in maintaining an overall reducing environment within the cell. The classical functionality of Trx underlies donating hydrogen group to ribonucleotide reductase (RNR) for catalysis and conversion of nucleotides to deoxynucleotides [4, 18, 19]. The disulfide formed at the active site (R1 subunit) of the RNR during catalysis is reduced by the C-Terminal swinging arm of the R1 subunit via accepting electrons from Trx [4, 5]. Thus, to support this catalytic cycle Trx needs to remain in its reduced form during each catalytic cycle with the help of TrxR. It has been found that cancer cells over-expresses Trx and TrxR, thus inhibiting TrxR activity might show a therapeutic promise in cancer [6, 7]. However, this is not the case and the classical TrxR inhibitors ATG (aurothioglucose) and auranofin (AF) that have been extensively used in numerous studies as pharmacological inhibitors of TrxR was not successful in killing cancer cells . The study conducted by Du et al., 2012  showed that physiological concentration of GSH, NADPH and glutathione reductase reduced Trx-1, which was further enhanced upon addition of glutaredoxin (Grx) to the system. This irrefutably supports that survival of TrxR1-/- tumors were strictly dependent on a functional GSH system to reduce oxidized Trx1 and thus TrxR1-/- cells were susceptible to pharmacological GSH deprivation [7-9]. However, no such study showed to date if GSH-mediated Trx1 reduction can aid in electron donation to support RNR catalysis in absence of TrxR1. Herein, we present a first cell-free study report that GSH-mediated Trx reduction can bypass the need of TrxR and support RNR catalysis in absence of TrxR1. Likewise, the cytosol is endowed with other direct and indirect antioxidant systems such as the lipoic acid (LA) and lipoamide system (LAM) comprising of Lipoamide (LAM), lipoamide dehydrogenase (LD), and reducing equivalent NADH [10, 13, 14]. It is well noted that TrxR and NADPH can also reduce oxidized LAM independent of LD and NADH [11,12]. Here, we have found for the first time that LAM is also capable of directly reducing the disulfide formed at the catalytic subunit of RNR and support RNR activity in absence of TrxR/Trx by utilizing LD and NADH. Thus, we rationalize that these widespread redundancies between the various antioxidant systems in the cell might potentially constrain chemotherapeutic treatments and contribute to cancer resistance. Thus, our data behold on concomitantly targeting/inhibiting multiple antioxidant systems within the cell might synergize in killing tumor cells and rule out to have a promising future implication in cancer.