Posttranslational oxidation of SOD1 and skin aging: Evidence, gaps, and future directions.

As the body's primary barrier against environmental insults, the skin is continually exposed to oxidative stress, which may contribute to progressive proteotoxic stress. Excess reactive oxygen species (ROS) can overwhelm cellular protein-quality-control systems, promoting the accumulation of damaged and misfolded proteins, proteome instability, and eventual Protein homeostasis (proteostasis(definition)) collapse. Superoxide dismutase 1 (SOD1), a Cu/Zn-dependent cytosolic antioxidant enzyme and key component of cellular defense against superoxide radicals, is itself vulnerable to oxidative modification. ROS-mediated post-translational oxidation of SOD1 may promote its misfolding and the formation of toxic protein species, potentially establishing a self-amplifying cycle of superoxide accumulation, further protein damage, and impaired cellular homeostasis. In cutaneous cell types, including dermal fibroblasts and epidermal cells, these processes may be especially relevant to age-associated declines in proteostatic capacity and skin aging. This review distinguishes established skin-specific evidence from hypotheses extrapolated from other systems and synthesizes current evidence on the interplay among ROS-induced protein damage, proteostasis failure, SOD1 dysfunction, and cutaneous aging. We highlight the bidirectional relationship between proteostasis collapse and mitochondrial dysfunction(definition), which may establish a self-reinforcing cycle of oxidative stress, cellular senescence(definition), and chronic low-grade inflammation. These interconnected processes may converge to promote extracellular-matrix remodeling and tissue dysfunction, contributing to wrinkles, reduced elasticity, and impaired barrier function. By positioning SOD1 oxidation as a potential contributor to cutaneous proteostatic dysfunction, this review provides a framework for evaluating whether the SOD1 proteotoxic axis represents a candidate therapeutic target for skin aging.