UVB-induced keratinocyte disulfidptosis drives skin photodamage and photoaging

Environmental stressors challenge cellular homeostasis, yet how they corrupt proteostasis to drive tissue injury remains incompletely defined. Here, we report that aberrant accumulation of disulfide-crosslinked proteins, a hallmark of disulfide stress, acts as a novel, actionable molecular lesion in ultraviolet B (UVB)-induced skin photodamage and photoaging. This lesion executes disulfidptosis, a recently discovered form of regulated cell death. We demonstrate that disulfide stress acts as a quantifiable pathogenic continuum, linking acute UVB insult to chronic tissue degeneration in skin. Core biochemical features of disulfidptosis, including NADPH depletion, excessive disulfide-bond formation, and F-actin collapse, were consistently observed in human keratinocytes from physiologically relevant systems: sun-exposed skin, ex vivo UVB-irradiated skin, and keratinocytes cultured in vitro. Genetic and pharmacological interrogation across murine models of chronic and acute injury established NCKAP1 as an essential mediator and revealed that inhibition of this pathway (via the reducing agent TCEP) robustly mitigates keratinocyte death and tissue damage. Our work defines UVB-induced disulfide stress and NCKAP1-mediated disulfidptosis as a previously unrecognized proteotoxic axis in environmental skin disease. We posit that disulfide-bond dyshomeostasis may represent a targetable vulnerability in a range of age-related and environmental pathologies characterized by proteostasis collapse, offering a new paradigm for therapeutic intervention beyond dermatology.