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Background <p>Ultraviolet B (UVB) radiation-induced skin damage involves complex molecular mechanisms, yet the protective factors that maintain keratinocyte homeostasis remain incompletely understood. N-myc downstream-regulated gene 2 (NDRG2), a stress-responsive tumor suppressor, has emerged as a critical regulator of cellular oxidative stress responses, but its role in skin photoprotection is unknown.</p> Objective <p>To investigate the expression, regulation, and functional significance of NDRG2 in human keratinocytes and elucidate its protective mechanisms against UVB-induced photodamage.</p> Methods <p>Stable NDRG2-knockdown HaCaT keratinocyte cell lines were generated using lentiviral shRNA transfection. Baseline cellular functions including proliferation (EdU incorporation) and migration (wound healing) were assessed under normal conditions, along with basal Nrf2 expression. Following UVB irradiation (750&#xa0;mJ/cm²), we evaluated cell viability (CCK-8), apoptosis (flow cytometry), oxidative stress markers (SOD, CAT, GSH, MDA), and inflammatory mediators (TNF-α, IL-1β, IL-6) using biochemical assays and ELISA. UVB-responsive signaling proteins (HO-1, NQO1, NF-κB) were analyzed by Western blotting and immunofluorescence microscopy. To validate the role of antioxidant defenses, N-acetylcysteine (NAC) rescue experiments were performed in NDRG2-deficient cells.</p> Results <p>NDRG2 depletion significantly impaired fundamental keratinocyte functions, reducing proliferation and migration capacity. UVB irradiation induced biphasic NDRG2 expression kinetics: acute suppression at 3–6&#xa0;h followed by compensatory upregulation at 24–48&#xa0;h. Critically, NDRG2 deficiency exacerbated UVB-induced photodamage, manifested by enhanced cell death and increased apoptosis. Mechanistically, NDRG2 knockdown compromised antioxidant defense capacity, evidenced by significant reductions in enzymatic activities of SOD, CAT, and GSH. Concurrently, lipid peroxidation (MDA) increased, while inflammatory cytokine production was markedly enhanced (TNF-α, IL-6, and IL-1β). Importantly, NDRG2 depletion significantly reduced basal Nrf2 expression and impaired UVB-induced activation of downstream cytoprotective genes HO-1 and NQO1, while promoting NF-κB-mediated inflammatory signaling. Furthermore, NAC treatment partially restored cell viability in UVB-irradiated NDRG2-knockdown cells, confirming that compromised antioxidant capacity contributes to the enhanced photodamage phenotype.</p> Conclusions <p>NDRG2 functions as an essential guardian of keratinocyte homeostasis and photoprotection through maintenance of Nrf2-mediated antioxidant capacity and suppression of inflammatory responses. These findings establish NDRG2 as a novel therapeutic target for preventing UV-induced skin photodamage and age-related skin disorders.</p>

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NDRG2 deficiency exacerbates UVB-induced photodamage in human keratinocytes via impaired Nrf2-mediated antioxidant defense

  • 期刊论文

  • 发表日期：

    2026年3月12日

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  • Yanan He,
  • Lu Yu,
  • Wei Wu,
  • Yanqi Li,
  • Wenjun Zhu,
  • Xian Zhang,
  • Yulong Ma,
  • Lixia Zhang

摘要

Background

Ultraviolet B (UVB) radiation-induced skin damage involves complex molecular mechanisms, yet the protective factors that maintain keratinocyte homeostasis remain incompletely understood. N-myc downstream-regulated gene 2 (NDRG2), a stress-responsive tumor suppressor, has emerged as a critical regulator of cellular oxidative stress responses, but its role in skin photoprotection is unknown.

Objective

To investigate the expression, regulation, and functional significance of NDRG2 in human keratinocytes and elucidate its protective mechanisms against UVB-induced photodamage.

Methods

Stable NDRG2-knockdown HaCaT keratinocyte cell lines were generated using lentiviral shRNA transfection. Baseline cellular functions including proliferation (EdU incorporation) and migration (wound healing) were assessed under normal conditions, along with basal Nrf2 expression. Following UVB irradiation (750 mJ/cm²), we evaluated cell viability (CCK-8), apoptosis (flow cytometry), oxidative stress markers (SOD, CAT, GSH, MDA), and inflammatory mediators (TNF-α, IL-1β, IL-6) using biochemical assays and ELISA. UVB-responsive signaling proteins (HO-1, NQO1, NF-κB) were analyzed by Western blotting and immunofluorescence microscopy. To validate the role of antioxidant defenses, N-acetylcysteine (NAC) rescue experiments were performed in NDRG2-deficient cells.

Results

NDRG2 depletion significantly impaired fundamental keratinocyte functions, reducing proliferation and migration capacity. UVB irradiation induced biphasic NDRG2 expression kinetics: acute suppression at 3–6 h followed by compensatory upregulation at 24–48 h. Critically, NDRG2 deficiency exacerbated UVB-induced photodamage, manifested by enhanced cell death and increased apoptosis. Mechanistically, NDRG2 knockdown compromised antioxidant defense capacity, evidenced by significant reductions in enzymatic activities of SOD, CAT, and GSH. Concurrently, lipid peroxidation (MDA) increased, while inflammatory cytokine production was markedly enhanced (TNF-α, IL-6, and IL-1β). Importantly, NDRG2 depletion significantly reduced basal Nrf2 expression and impaired UVB-induced activation of downstream cytoprotective genes HO-1 and NQO1, while promoting NF-κB-mediated inflammatory signaling. Furthermore, NAC treatment partially restored cell viability in UVB-irradiated NDRG2-knockdown cells, confirming that compromised antioxidant capacity contributes to the enhanced photodamage phenotype.

Conclusions

NDRG2 functions as an essential guardian of keratinocyte homeostasis and photoprotection through maintenance of Nrf2-mediated antioxidant capacity and suppression of inflammatory responses. These findings establish NDRG2 as a novel therapeutic target for preventing UV-induced skin photodamage and age-related skin disorders.