Authors
Rui Zhou, Mücahit Varlı, Rundong Liu, Jieun Yu, Hyung-Ho Ha, Jae-Seoun Hur, Sang Kyum Kim, Hahyun Park, Hangun Kim
Published in
Cell proliferation. Pages e70279. Sep 27, 2026. Epub Sep 27, 2026.
Abstract
Gliomas remain among the most lethal brain tumours, driven by aggressive invasion, stem-like properties, metabolic plasticity, and frequent resistance to temozolomide (TMZ). Hypoxia-inducible factor-1α (HIF-1α) is a central regulator of these malignant traits. In this study, we identify methyl 4-O-demethylbarbatate (Me-4-O-DBA), a biosynthetically produced lichen-derived metabolite, as a potential modulator of HIF-1α signaling. Molecular docking analysis suggested a possible interaction between Me-4-O-DBA and HIF-1α near the Lys304 ubiquitination site, which may contribute to reduced HIF-1α stability and suppression of downstream EMT and stemness signaling. This inhibition simultaneously attenuated both glycolytic activity and mitochondrial respiration, indicating a broad suppression of metabolic reprogramming. Network pharmacology and molecular docking further indicated HIF-1α-associated signaling as a potential regulatory hub, while in vitro assays demonstrated marked reductions in glioma cell viability, invasion, migration, and clonogenicity. Notably, Me-4-O-DBA synergised with TMZ to enhance suppression of motility, stemness, and metabolic activity, resulting in profound impairment of tumourigenic potential. In vivo zebrafish assays also indicated a favourable safety profile at the tested concentrations. Together, these findings suggest that Me-4-O-DBA suppresses HIF-1α-associated malignant phenotypes and enhances TMZ responsiveness in glioma cells, highlighting its potential as a natural product-derived modulator of glioma progression.
PMID:
42802108
Bibliographic data and abstract were imported from PubMed on 28 Sep 2026.
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