USP10-SIRT6-PARP1 axis drives keratinocyte senescence and skin photoaging under chronic UVA exposure.
Level 5 - mechanism / opinion, no new human data
Preclinical laboratory research (cultured human cells and mouse model)
PubMed 42537350 · doi:10.1016/j.intimp.2026.117222
What was done
Researchers investigated the mechanisms of ultraviolet A (UVA)–induced skin photoaging using cultured human keratinocytes and a chronic UVA irradiation mouse model. They examined sirtuin family expression, protein degradation pathways involving the deubiquitinase USP10, downstream DNA-damage signaling via PARP1, and cellular senescence markers. In addition, they tested whether pharmacological activation of SIRT6 using the selective agonist UBCS039 or the plant-derived coumarin osthole could reverse UVA-induced cellular senescence and inflammatory responses.
What was found
The abstract reports qualitative molecular and phenotypic directions without numeric values or effect sizes. UVA exposure induced DNA damage, G2/M cell-cycle arrest, and selective depletion of SIRT6 via transcriptional and post-transcriptional suppression of USP10, leading to ubiquitin-dependent proteasomal degradation of SIRT6. Loss of SIRT6 resulted in PARP1 hyperactivation, accelerated senescence, and increased chemokine and cytokine secretion. Pharmacological activation of SIRT6 with UBCS039 attenuated DNA damage, senescence markers, epidermal hyperplasia, and inflammatory mediators in vitro and in vivo. Molecular docking and functional validation also identified osthole as a candidate SIRT6-activating compound that reduced UVA-induced senescence.
Why it matters
The study delineates the USP10-SIRT6-PARP1 signaling pathway as a driver of UVA-induced keratinocyte senescence and demonstrates that targeting SIRT6 activation can counteract photoaging phenotypes in preclinical models.
Limits
The abstract reports no quantitative data, sample sizes, animal numbers, dosing regimens, or statistical certainty measures. Findings are restricted to in vitro human cell cultures and mouse models; clinical efficacy and safety of UBCS039 or osthole for human skin photoaging remain unproven.
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