A novel approach to target skin photodamage: Topical application of salt inducible kinase inhibitors.

Background: Ultraviolet (UV) radiation accelerates skin damage and photoageing, leading to visible signs such as wrinkles, loss of elasticity and uneven pigmentation. UV radiation causes direct DNA damage, primarily through the formation of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs), which can lead to mutations and cellular dysfunction if not repaired. While natural defence mechanisms like melanin production and DNA repair pathways mitigate this damage, prolonged or excessive UV exposure can overwhelm these defences, resulting in cumulative skin damage. The melanocortin 1 receptor (MC1R) plays a key role in melanogenesis and also appears to play a role in DNA repair. Salt-inducible kinases (SIKs), critical enzymes in the MC1R pathway, are known to influence melanin production, but their role in DNA repair and photodamage remains unclear.

Objective: This study investigated the role of SIK in DNA repair and photodamage, focusing on two novel cosmetic ingredients, SIK inhibitors, coded SLT-008 and SLT-001.

Methods: The inhibitory effects of the ingredients on SIK activity were measured using biochemical and cellular assays. Their safety profiles were evaluated through in vitro studies and clinical trials. To analyse their impact on UV-B-induced DNA damage and repair, both inhibitors were topically applied to skin extracts in an ex vivo model. Finally, clinical studies were conducted in healthy volunteers irradiated with UV-R. Efficacy was determined by measuring CPD levels, matrix metalloproteinase-1 (MMP-1), expression and erythema formation following UV exposure.

Results: Both ingredients effectively inhibited SIK activity and demonstrated good safety profiles. Ex vivo experiments revealed that immediate post-UV-B application of both ingredients significantly reduced UV-B-induced DNA damage, as shown by decreased CPDs, and promoted tissue repair. Additionally, both inhibitors suppressed MMP-1 expression, an enzyme that plays a key role in the breakdown of collagen, thereby accelerating photoageing. These findings were confirmed in the clinical study, which demonstrated that topically applied SLT-001 enhanced DNA repair, reduced MMP-1 expression and decreased erythema formation.

Conclusion: Here we described the comprehensive role of SIK inhibition in DNA and dermal repair. This highlights its crucial role in protecting skin against UV-induced photodamage and offering broad protection against actinic ageing.