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<p>Cellular senescence in dermal fibroblasts, a hallmark of skin aging, involves progressive mitochondrial dysfunction, elevated oxidative stress, and reduced regenerative potential. While the RNA-binding protein Lin28a has shown promise in regulating cellular homeostasis, its therapeutic application is hindered by poor cellular uptake and rapid degradation. To overcome these limitations, this study reports the design and functional validation of 30Kc19α-Lin28a, a recombinant protein created by conjugating Lin28a to the silkworm-derived cell-penetrating protein 30Kc19α. The fusion protein efficiently translocated into human dermal fibroblasts (HDFs), with detectable levels maintained for 24–48&#xa0;h post-treatment. In HDFs undergoing replicative senescence, 30Kc19α-Lin28a significantly enhanced proliferation and migration while attenuating senescence phenotypes, as evidenced by decreased senescence-associated β-galactosidase activity and downregulated expression of <i>p16</i>, <i>p21</i>, and <i>p53</i>. Mechanistically, 30Kc19α-Lin28a ameliorated mitochondrial dysfunction by restoring membrane potential and markedly reduced intracellular reactive oxygen species accumulation. Although these results demonstrate the potential of 30Kc19α-Lin28a as an anti-senescence agent for dermal applications, future studies are necessary to ascertain in vivo effectiveness. Collectively, 30Kc19α-Lin28a represents a promising protein-based strategy targeting mitochondrial function and redox balance to mitigate senescence in dermal fibroblasts.</p>

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Recombinant 30Kc19α-Lin28a fusion protein enhances mitochondrial function and attenuates senescence in human dermal fibroblasts

  • 期刊论文

  • 发表日期：

    2025年9月2日

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  • Chanho Lee,
  • Ju Hyun Park

摘要

Cellular senescence in dermal fibroblasts, a hallmark of skin aging, involves progressive mitochondrial dysfunction, elevated oxidative stress, and reduced regenerative potential. While the RNA-binding protein Lin28a has shown promise in regulating cellular homeostasis, its therapeutic application is hindered by poor cellular uptake and rapid degradation. To overcome these limitations, this study reports the design and functional validation of 30Kc19α-Lin28a, a recombinant protein created by conjugating Lin28a to the silkworm-derived cell-penetrating protein 30Kc19α. The fusion protein efficiently translocated into human dermal fibroblasts (HDFs), with detectable levels maintained for 24–48 h post-treatment. In HDFs undergoing replicative senescence, 30Kc19α-Lin28a significantly enhanced proliferation and migration while attenuating senescence phenotypes, as evidenced by decreased senescence-associated β-galactosidase activity and downregulated expression of p16, p21, and p53. Mechanistically, 30Kc19α-Lin28a ameliorated mitochondrial dysfunction by restoring membrane potential and markedly reduced intracellular reactive oxygen species accumulation. Although these results demonstrate the potential of 30Kc19α-Lin28a as an anti-senescence agent for dermal applications, future studies are necessary to ascertain in vivo effectiveness. Collectively, 30Kc19α-Lin28a represents a promising protein-based strategy targeting mitochondrial function and redox balance to mitigate senescence in dermal fibroblasts.