Notoginsenoside R1 Mitigates UVB-induced Skin Sunburn Injury through Modulation of N4-acetylcytidine and Macroautophagy

Background Panax Notoginseng Saponins (PNS) have exhibited therapeutic effects in the repair of skin photoaging induced by UVB radiation; however, the precise mechanism of action remains to be elucidated. Purpose This study is designed to utilize network pharmacology prediction methods to explore the mechanisms by which PNS repair UVB-induced skin photoaging. Furthermore, the chemical composition of PNS was characterized using UHPLC-Q-Orbitrap-MS/MS. An in-depth analysis of the pharmacodynamics of a specific component of PNS, Notoginsenoside R1 (NGR1), was also performed. Methods Qualitative and quantitative analyses were conducted utilizing UHPLC-Q-orbitrap-MS/MS and UHPLC-Q-Trap-MS/MS to investigate the chemical constituents of PNS. Furthermore, network pharmacology predictions were employed to explore the key targets and mechanisms by which PNS mitigates UVB-induced skin sunburn injury. Furthermore, a nude mouse model was employed to validate the therapeutic efficacy of PNS and its constituent NGR1, whereas HaCaT cells were utilized to elucidate their target mechanisms. Results This study was designed to thoroughly examine the fundamental mechanisms responsible for the efficacy of PNS in alleviating UVB-induced skin sunburn injury. Additionally, 16 primary saponin components within PNS were identified and subjected to quantitative analysis. Network pharmacology methodologies were utilized to identify 49 key targets of PNS in alleviating UVB-induced skin photoaging. Administration of PNS and NGR1 ameliorates UVB-induced photoaging symptoms through the reduction of inflammation, enhancement of antioxidant defense, inhibition of PI3K/AKT/mTOR signaling pathway activation, and regulation of cellular homeostasis proteins. Furthermore, it provides protection against apoptosis in HaCaT cells by upregulating essential cellular homeostasis proteins, such as p62, while concurrently downregulating autophagy-related proteins, including Beclin-1 and LC3-II. NAT10 expression is reduced by UVB radiation; however, this reduction can be reversed by the administration of drugs PNS and NGR1. The autophagy pathway, which is regulated by NBR1 and p62, is likely involved in the degradation of NAT10 under both physiological and UVB-induced conditions. Conclusion The potential of PNS and NGR1 in skin sunburn injury therapies is evidenced by their capability to mitigate UVB-induced skin damage via the inhibition of PI3K/AKT/mTOR signaling pathway activation, the reduction of cellular apoptosis and autophagy, and the enhancement of RNA acetyl transferase NAT10 regulation. The findings not only lay robust groundwork for subsequent clinical trials of PNS and NGR1 ointment but also furnish compelling evidence to elucidate the therapeutic mechanisms of PNS and NGR1 in the prevention and treatment of UVB-induced skin sunburn injury.