SUMOylation in skin homeostasis and disease: Regulation of cutaneous signaling networks.

SUMOylation is a reversible post-translational modification that regulates protein stability, subcellular localization, molecular interactions, and transcriptional activity. The skin is constantly exposed to ultraviolet radiation and other environmental stressors, yet it must maintain barrier function and restore tissue homeostasis. This review examines how SUMOylation contributes to cutaneous stress responses by linking cellular damage, inflammation, and tissue repair. By altering the fate and function of stress-responsive proteins, SUMOylation shapes the strength and duration of damage responses and inflammatory signaling. Its effects vary with the substrate, cell type, and disease context. SUMOylation can support DNA repair and adaptive stress responses, but under other conditions it can sustain inflammatory or pro-survival programs. Dysregulated SUMOylation or deSUMOylation of specific proteins may prolong inflammatory signaling, disrupt epidermal homeostasis, and impair tissue repair. These changes may contribute to chronic inflammation, fibrosis, and skin tumor progression. Current evidence is strongest for defined mechanisms in keratinocytes, melanocytic cells, fibroblast activation, and skin tumors, whereas several proposed links to inflammatory and metabolic skin diseases remain incompletely established. The biological effects of SUMOylation cannot be explained by changes in overall SUMO conjugation alone. Instead, they arise from specific interactions between SUMO enzymes and their substrates within distinct cellular environments. Clinical evaluation of SUMO-pathway inhibition has so far focused largely on oncology. This context dependence limits the value of broadly inhibiting the SUMO system, as such treatment may also interfere with its normal protective functions. A more precise therapeutic strategy may be to identify disease-relevant SUMO enzyme-substrate interactions and selectively modulate them in specific cell types or affected areas of the skin.