PDRN Blocks Autophagy to Shield Key Anti-Aging Protein SIRT1 in Skin Cells

Skin aging driven by UV radiation and oxidative stress is a major dermatological concern, yet the molecular mechanisms linking environmental stressors to cellular senescence remain incompletely understood. SIRT1, an NAD+-dependent deacetylase, is a well-established regulator of aging, inflammation, and DNA repair, but its levels decline with age and under oxidative stress—partly because it is shuttled from the nucleus to the cytoplasm and degraded via autophagosome-lysosome pathways. This study investigated whether PDRN, a low-molecular-weight polynucleotide approved for tissue repair, could counteract this process.

Researchers exposed human keratinocytes (HaCaT) and human dermal fibroblasts (HDF) to either UVB radiation (300 mJ/cm²) or hydrogen peroxide (250 µM) to induce cellular senescence, then treated cells with PDRN. In parallel, a mouse model received repeated UVB irradiation (200 mJ/cm² daily for four weeks) with or without intraperitoneal PDRN injections. Outcomes were assessed via CCK-8 viability assays, SA-β-galactosidase staining, flow cytometry for apoptosis, wound-healing scratch assays, RT-PCR for senescence genes, immunoblotting, nuclear/cytoplasmic fractionation, and immunofluorescence.

PDRN treatment significantly improved cell viability and migration after both UVB and H₂O₂ insults, and reduced the proportion of SA-β-gal-positive (senescent) cells. At the molecular level, PDRN suppressed the upregulation of senescence markers p16, p21, and p53, and reduced MMP1 expression. Critically, PDRN prevented the nuclear accumulation of LC3—a key autophagy mediator—and blocked the cytoplasmic degradation of SIRT1 and the autophagy receptor p62. Immunofluorescence confirmed that PDRN reduced cytoplasmic stress granule formation. In mice, PDRN treatment visibly attenuated UVB-induced epidermal thickening as shown by H&E histology.

The mechanistic picture that emerges is that oxidative or UV stress triggers nuclear autophagy (nucleophagy), causing LC3 to accumulate in the nucleus and facilitating SIRT1 export and degradation in the cytoplasm. PDRN interrupts this cascade by reducing LC3 accumulation and thereby preserving SIRT1 protein levels—without significantly altering SIRT1 mRNA, suggesting the protection is post-transcriptional. This is a novel mechanism distinct from previously described transcriptional regulation of SIRT1.

The study adds to growing evidence that PDRN's pharmacological benefits extend beyond its known roles as an A2A receptor agonist and DNA salvage pathway substrate. The dual in vitro and in vivo validation strengthens confidence in the findings, though the work is early-stage and several questions remain open regarding dose optimization, long-term safety, and translation to human clinical use.