Monoterpenoids from the Roots of Liquidambar formosana (Formosan Sweet Gum) Exhibit Senomorphic Activity Against...

Cellular senescence is a hallmark of aging that contributes to tissue dysfunction and age-related diseases. This process is characterized by the activation of the cyclin-dependent kinase inhibitor p16^INK4A and the secretion of pro-inflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). In this study, we used human lung-derived cells, including A549 and IMR90 fibroblasts, to identify bioactive compounds from the roots of Liquidambar formosana that suppress p16^INK4A activity and attenuate SASP expression.

Bioactivity-guided isolation was performed to obtain target compounds. The structures of the new compounds were elucidated using extensive 1D and 2D NMR spectroscopic analyses as well as high-resolution mass spectrometry. All isolated compounds were evaluated for their ability to inhibit p16^INK4A, a key regulator of the cell cycle and an important tumor suppressor protein.

Two previously undescribed monoterpenoids (1 and 2), characterized as cinnamic acid esters with a monoterpene-derived core, were isolated from the roots of L. formosana, along with six known compounds (3-8). Notably, compound 3 exhibited promising inhibition of p16^INK4A with an IC₅₀ value of 3.9 μM. Furthermore, this compound attenuated the senescence phenotype, as demonstrated by β-galactosidase staining and RT-qPCR analysis. This represents the first report identifying bioactive monoterpenoids from L. formosana that inhibit aging-related biomarkers such as p16^INK4A.

These results suggest that cinnamic acid-conjugated monoterpenoids may serve as interesting lead structures for the development of agents targeting the p16^INK4A pathway for the treatment of aging-associated diseases. Further studies will be required to clarify the mechanisms of action of this compound and to evaluate its in vivo efficacy.