{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T07:38:23Z","timestamp":1761550703625,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT in Korea","award":["RS-2022-NR070150","RS-2023-00218616"],"award-info":[{"award-number":["RS-2022-NR070150","RS-2023-00218616"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/objectives: 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 p16INK4A 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 p16INK4A activity and attenuate SASP expression. Methods: 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 p16INK4A, a key regulator of the cell cycle and an important tumor suppressor protein. Results: 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\u20138). Notably, compound 3 exhibited promising inhibition of p16INK4A with an IC50 value of 3.9 \u03bcM. Furthermore, this compound attenuated the senescence phenotype, as demonstrated by \u03b2-galactosidase staining and RT-qPCR analysis. This represents the first report identifying bioactive monoterpenoids from L. formosana that inhibit aging-related biomarkers such as p16INK4A. Conclusions: These results suggest that cinnamic acid-conjugated monoterpenoids may serve as interesting lead structures for the development of agents targeting the p16INK4A 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.<\/jats:p>","DOI":"10.3390\/nu17213321","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T02:03:48Z","timestamp":1761185028000},"page":"3321","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Monoterpenoids from the Roots of Liquidambar formosana (Formosan Sweet Gum) Exhibit Senomorphic Activity Against Cellular Senescence"],"prefix":"10.3390","volume":"17","author":[{"given":"Minh Thi Tuyet","family":"Le","sequence":"first","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quang Huy","family":"Vu","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5077-2899","authenticated-orcid":false,"given":"Van-Hieu","family":"Mai","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9058-7727","authenticated-orcid":false,"given":"Jorge Eduardo","family":"Ponce-Zea","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seri","family":"Choi","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7143-9497","authenticated-orcid":false,"given":"Jin-Pyo","family":"An","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0761-3064","authenticated-orcid":false,"given":"Won-Keun","family":"Oh","sequence":"additional","affiliation":[{"name":"Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1038\/s41597-024-03924-7","article-title":"Chromosome-level genome assembly of American sweetgum (Liquidambar styraciflua, Altingiaceae)","volume":"11","author":"Ma","year":"2024","journal-title":"Sci. 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