Securinega alkaloids from the twigs of Flueggea suffruticosa as novel modulators of the skin circadian clock.

Circadian rhythms manage essential physiological processes in the skin, and their disruption is linked to impaired epidermal homeostasis. Despite the potential of natural products as circadian modulators, medicinal plant-derived metabolites remain insufficiently explored. Following the discovery of the circadian-modulating potential in the MeOH extract and its fractions, we investigated the twigs of Flueggea suffruticosa to identify the bioactive compounds. LC-UV/MS and bioactivity-guided phytochemical investigation led to the identification of four new Securinega alkaloids, securingines J-M (1-4), along with thirteen known compounds (5-17). Their structures were elucidated by the analysis of NMR, HR-ESIMS, ECD calculations, and DP4+ probability. In HaCaT keratinocytes, 7, 10, and 11 significantly altered the period and amplitude of the BMAL1-driven molecular clock. These phenotypes were supported by in silico docking to cryptochrome proteins and validated by the transcriptional regulation of CRY1 and PER2 mRNA expression. Our study expands the chemical diversity of F. suffruticosa-derived alkaloids and establishes their potential as natural modulators of keratinocyte circadian rhythms, representing the first definitive report linking Securinega alkaloids to skin chronobiology.