Notoginsenoside R1 mitigates UVB-induced skin sunburn injury through modulation of N(4)-acetylcytidine and autophagy.

BACKGROUND: In recent years, skin sunburn injury caused by UVB has become a growing concern. Although PNS have demonstrated potential in alleviating this condition, the precise mechanisms involved remain incompletely elucidated. PURPOSE: This study was designed with three primary objectives. First, to apply network pharmacology-based predictive approaches to elucidate the mechanisms underlying PNS-mediated protection against UVB-induced skin sunburn injury. Second, to systematically analyze the chemical profile of PNS through UHPLC-Q-Orbitrap-MS/MS. Third, to conduct a comprehensive assessment of the pharmacodynamic properties of NGR1, a major bioactive constituent of PNS. METHODS: The chemical constituents of PNS were analyzed qualitatively and quantitatively using UHPLC and UHPLC-Q-Trap-MS/MS. Network pharmacology approaches were employed to identify the core molecular targets and potential mechanisms through which PNS alleviates UVB-induced sunburn injury. To evaluate the therapeutic effects of PNS and NGR1, an in vivo model was established using nude mice, while mechanistic studies were conducted in HaCaT cells to elucidate the underlying signaling pathways. RESULTS: A total of 16 primary saponins in PNS were successfully identified and quantified. Through network pharmacology analysis, 49 crucial molecular targets associated with PNS in the context of UVB-induced skin sunburn injury were revealed. Treatment with PNS and NGR1 ameliorated signs of photoaging via multiple mechanisms, including suppression of inflammatory responses, boosting antioxidant capacity, inhibition of the PI3K/AKT/mTOR signaling cascade, and regulation of proteins involved in maintaining cellular homeostasis. In HaCaT cells, PNS and NGR1 exert protective effects against apoptosis by modulating proteins associated with cellular homeostasis and autophagy. Both compounds counteracted the UVB-induced reduction in NAT10 expression. The degradation of NAT10, potentially mediated by the autophagy pathway involving key selective adaptors such as NBR1 and p62, may occur under both basal and UVB-exposed conditions. CONCLUSION: PNS and NGR1 demonstrate promising therapeutic potential for the treatment of UVB-induced skin sunburn injury. Their capacity to mitigate photodamage via multiple mechanisms, such as inhibition of key signaling pathways, regulation of apoptosis and autophagy, and modulation of NAT10 expression, lays a strong foundation for future clinical studies on topical applications of PNS and NGR1, while also providing valuable insights into their preventive and curative effects.