ABSTRACT Fibroblasts are essential for tissue repair, but reactive oxygen species (ROS) can impair their function, leading to mitochondrial dysfunction and apoptosis. γ‐Glutamylcysteine (γ‐GC), a glutathione (GSH) precursor and potent antioxidant, may protect fibroblasts, though its mechanisms in ROS‐mediated damage remain unclear. This study examined γ‐GC's effects on tert‐butyl hydroperoxide (t‐BHP)‐injured NIH/3T3 fibroblasts. γ‐GC effectively reduced ROS levels, restored antioxidant defenses, and preserved mitochondrial function, thereby inhibiting apoptosis. Mechanistically, γ‐GC upregulated nuclear factor erythroid 2‐related factor 2 (Nrf2) and promoted its nuclear translocation. The Nrf2 inhibitor ML385 confirmed that γ‐GC's protective effects were mediated through Nrf2 activation. These results demonstrate that γ‐GC, as a direct GSH precursor, not only scavenges ROS but also enhances cellular antioxidant capacity and mitochondrial homeostasis. Its dual role in ROS mitigation and Nrf2 activation highlights γ‐GC's therapeutic potential for improving aberrant tissue repair.
Lu et al. (Sun,) studied this question.