{"doi":"10.1016/j.sciaf.2025.e02709","title":"Flavonoids from the leaves of Monanthotaxis filipes modulate PCSK9 and LDLR","abstract":"Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in the regulation of blood cholesterol levels. Its inhibition attenuates hypercholesterolemia and hence is a viable approach for the management of atherosclerotic cardiovascular disease (ASCVD). We evaluated the flavonoids of the leaves of Monanthotaxis filipes P.H. Hoekstra (Annonaceae) for their effect on PCSK9 and low-density lipoprotein receptor (LDLR) expression at the mRNA level in HepG2 cells using quantitative real-time PCR analysis and for their influence on protein expression by ELISA. Six flavonoids, including two chalcones ( 1, 5 ), three flavones ( 2 – 4 ), and one flavanone ( 6 ), were isolated by chromatographic techniques and identified by spectroscopic (NMR, IR, UV, MS) analyses. 2′,3′,4′,6′-Tetramethoxychalcone ( 1 ) reduced the PCSK9 protein amount and altered LDLR both on mRNA and protein levels, 6,7,8-trimethoxyflavone ( 2 ) inhibited PCSK9 both on mRNA and protein levels but did not change the amount of LDLR in HepG2 cells, whereas 2ʹ,4ʹ-dihydroxy-6ʹ-methoxy-3ʹ,5ʹ-dimethylchalcone ( 5 ) decreased PCSK9 and upregulated LDLR protein expression. Thus, chalcones 1 and 5 , flavones 2 – 4 , and flavanone 6 were shown to be promising compounds for the management of cardiovascular disease. Molecular dynamics simulations suggest that an allosteric mechanism underlies the inhibitory effect of 2 on PCSK9. In contrast, the pronounced activity of 5 is due to the interaction of its benzene ring with the Cys358, Pro438, Val460 and Trp461 residues of the catalytic site, as proposed by Molecular Mechanics Poisson Boltzmann surface area (MM-PBSA) analyses. Our results showed that chalcone 5 might be studied further for the management of atherosclerotic cardiovascular disease (ASCVD).","journal":"Scientific African","year":2025,"id":564328,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9565,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1467355,"name":"Yoseph Atilaw","orcid":"0000-0003-2899-9912","position":1,"is_corresponding":false},{"id":1467356,"name":"Daniel M. Shadrack","orcid":"0000-0002-4436-1487","position":2,"is_corresponding":false},{"id":1380645,"name":"Farkas Sarnyai","orcid":"0000-0002-5525-5508","position":3,"is_corresponding":false},{"id":1467357,"name":"Miklós Csala","orcid":"0000-0002-3829-4361","position":4,"is_corresponding":false},{"id":882557,"name":"Krisztína Németh","orcid":"0000-0002-3825-2137","position":5,"is_corresponding":false},{"id":1467358,"name":"Stephen S. Nyandoro","orcid":"0000-0002-4659-0187","position":6,"is_corresponding":false},{"id":1467359,"name":"Viola Tamási","orcid":"0000-0001-7419-5603","position":7,"is_corresponding":false},{"id":578672,"name":"Máté Erdélyi","orcid":"0000-0003-0359-5970","position":8,"is_corresponding":false},{"id":1467360,"name":"Joan J. E. Munissi","orcid":"0000-0003-1505-6309","position":9,"is_corresponding":false},{"id":1467705,"name":"James G. Mayeka","orcid":null,"position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:56:20.933088Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}