{"doi":"10.1111/bcpt.12572","title":"Myricetin Selectively Induces Apoptosis on Cancerous Hepatocytes by Directly Targeting Their Mitochondria","abstract":"<jats:title>Abstract</jats:title><jats:p>Hepatocellular carcinoma (<jats:styled-content style=\"fixed-case\">HCC</jats:styled-content>) is the third most common cause of cancer‐related death. In patients for whom <jats:styled-content style=\"fixed-case\">HCC</jats:styled-content> could not be detected early, current treatments show poor tolerance and low efficacy. So, alternative therapies with good efficacy are urgently needed. The aim of this research was to evaluate the selective apoptotic effects of myricetin (<jats:styled-content style=\"fixed-case\">MYR</jats:styled-content>), a flavonoid compound, on hepatocytes and mitochondria obtained from the liver of <jats:styled-content style=\"fixed-case\">HCC</jats:styled-content> rats. In this study, <jats:styled-content style=\"fixed-case\">HCC</jats:styled-content> induced by diethylnitrosamine (<jats:styled-content style=\"fixed-case\">DEN</jats:styled-content>), as an initiator, and 2‐acetylaminofluorene (2‐<jats:styled-content style=\"fixed-case\">AAF</jats:styled-content>), as a promoter. To confirm the <jats:styled-content style=\"fixed-case\">HCC</jats:styled-content> induction, serum levels of alpha‐fetoprotein (<jats:styled-content style=\"fixed-case\">AFP</jats:styled-content>), <jats:styled-content style=\"fixed-case\">AST</jats:styled-content>,<jats:styled-content style=\"fixed-case\"> AST</jats:styled-content> and <jats:styled-content style=\"fixed-case\">ALP</jats:styled-content> and histopathological changes in the liver tissue were evaluated. Rat liver hepatocytes and mitochondria for evaluation of the selective cytotoxic effects of <jats:styled-content style=\"fixed-case\">MYR</jats:styled-content> were isolated, and mitochondrial and cellular parameters related to apoptosis signalling were then determined. Our results showed that <jats:styled-content style=\"fixed-case\">MYR</jats:styled-content> was able to induce cytotoxicity only in hepatocytes from the <jats:styled-content style=\"fixed-case\">HCC</jats:styled-content> but not from the untreated control group. Besides, <jats:styled-content style=\"fixed-case\">MYR</jats:styled-content> (12.5, 25 and 50 μM) induced a considerable increase in reactive oxygen species (<jats:styled-content style=\"fixed-case\">ROS</jats:styled-content>) level, mitochondrial swelling, mitochondrial membrane permeabilization (<jats:styled-content style=\"fixed-case\">MMP</jats:styled-content>) and cytochrome c release only in cancerous but not in untreated normal hepatocyte mitochondria. <jats:styled-content style=\"fixed-case\">MYR</jats:styled-content> selectively increased caspase‐3 activation and apoptotic phenotypes in <jats:styled-content style=\"fixed-case\">HCC</jats:styled-content>, but not untreated normal hepatocytes. Finally, our finding underlines <jats:styled-content style=\"fixed-case\">MYR</jats:styled-content> as a promising therapeutic candidate against <jats:styled-content style=\"fixed-case\">HCC</jats:styled-content> and recommends the compound for further studies.</jats:p>","journal":"Basic &amp; Clinical Pharmacology &amp; Toxicology","year":2016,"id":661454,"datarank":0.611630616585858,"base_score":4.07753744390572,"endowment":4.07753744390572,"self_citation_contribution":0.611630616585858,"citation_network_contribution":0.0,"self_endowment_contribution":0.611630616585858,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":58,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1726767,"name":"Hamid Reza Rasekh","orcid":null,"position":1,"is_corresponding":false},{"id":1726768,"name":"Ahmad Salimi","orcid":null,"position":2,"is_corresponding":false},{"id":940027,"name":"Zhaleh Mohsenifar","orcid":"0000-0002-7766-7570","position":3,"is_corresponding":false},{"id":1726772,"name":"Jalal Pourahmad","orcid":null,"position":4,"is_corresponding":false},{"id":1726766,"name":"Enayatollah Seydi","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Myricetin Selectively Induces Apoptosis on Cancerous Hepatocytes by Directly Targeting Their Mitochondria","abstract":"<jats:title>Abstract</jats:title><jats:p>Hepatocellular carcinoma (<jats:styled-content style=\"fixed-case\">HCC</jats:styled-content>) is the third most common cause of cancer‐related death. In patients for whom <jats:styled-content style=\"fixed-case\">HCC</jats:styled-content> could not be detected early, current treatments show poor tolerance and low efficacy. So, alternative therapies with good efficacy are urgently needed. The aim of this research was to evaluate the selective apoptotic effects of myricetin (<jats:styled-content style=\"fixed-case\">MYR</jats:styled-content>), a flavonoid compound, on hepatocytes and mitochondria obtained from the liver of <jats:styled-content style=\"fixed-case\">HCC</jats:styled-content> rats. In this study, <jats:styled-content style=\"fixed-case\">HCC</jats:styled-content> induced by diethylnitrosamine (<jats:styled-content style=\"fixed-case\">DEN</jats:styled-content>), as an initiator, and 2‐acetylaminofluorene (2‐<jats:styled-content style=\"fixed-case\">AAF</jats:styled-content>), as a promoter. To confirm the <jats:styled-content style=\"fixed-case\">HCC</jats:styled-content> induction, serum levels of alpha‐fetoprotein (<jats:styled-content style=\"fixed-case\">AFP</jats:styled-content>), <jats:styled-content style=\"fixed-case\">AST</jats:styled-content>,<jats:styled-content style=\"fixed-case\"> AST</jats:styled-content> and <jats:styled-content style=\"fixed-case\">ALP</jats:styled-content> and histopathological changes in the liver tissue were evaluated. Rat liver hepatocytes and mitochondria for evaluation of the selective cytotoxic effects of <jats:styled-content style=\"fixed-case\">MYR</jats:styled-content> were isolated, and mitochondrial and cellular parameters related to apoptosis signalling were then determined. Our results showed that <jats:styled-content style=\"fixed-case\">MYR</jats:styled-content> was able to induce cytotoxicity only in hepatocytes from the <jats:styled-content style=\"fixed-case\">HCC</jats:styled-content> but not from the untreated control group. Besides, <jats:styled-content style=\"fixed-case\">MYR</jats:styled-content> (12.5, 25 and 50 μM) induced a considerable increase in reactive oxygen species (<jats:styled-content style=\"fixed-case\">ROS</jats:styled-content>) level, mitochondrial swelling, mitochondrial membrane permeabilization (<jats:styled-content style=\"fixed-case\">MMP</jats:styled-content>) and cytochrome c release only in cancerous but not in untreated normal hepatocyte mitochondria. <jats:styled-content style=\"fixed-case\">MYR</jats:styled-content> selectively increased caspase‐3 activation and apoptotic phenotypes in <jats:styled-content style=\"fixed-case\">HCC</jats:styled-content>, but not untreated normal hepatocytes. Finally, our finding underlines <jats:styled-content style=\"fixed-case\">MYR</jats:styled-content> as a promising therapeutic candidate against <jats:styled-content style=\"fixed-case\">HCC</jats:styled-content> and recommends the compound for further studies.</jats:p>","is_dataset_classified":null,"base_score":4.07753744390572,"endowment":4.07753744390572,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"26919160","pmcid":null,"openalex_id":"https://openalex.org/W2476612720","authors":[],"funders":[{"funder_name":"Shahid Beheshti University of Medical Sciences","grant_id":"1392‐1‐94‐11832","title":null}],"total_grants":1,"fwci":4.1678,"citation_percentile":0.94545599,"influential_citations":0,"citation_trend":[{"year":2016,"count":1},{"year":2017,"count":10},{"year":2018,"count":3},{"year":2019,"count":12},{"year":2020,"count":10},{"year":2021,"count":7},{"year":2022,"count":6},{"year":2023,"count":3},{"year":2024,"count":2},{"year":2025,"count":3},{"year":2026,"count":1}],"oa_status":"bronze","license":"http://onlinelibrary.wiley.com/termsAndConditions#vor","oa_locations":[{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/bcpt.12572","host_type":"journal"},{"url":"https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/bcpt.12572","host_type":"publisher"},{"url":"https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1111%2Fbcpt.12572","host_type":"publisher"},{"url":"https://onlinelibrary.wiley.com/doi/pdf/10.1111/bcpt.12572","host_type":"publisher"},{"url":"https://doi.org/10.1111/bcpt.12572","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/26919160","host_type":"repository"}],"fields_of_study":["Cell death mechanisms and regulation","Liver physiology and pathology","Drug-Induced Hepatotoxicity and Protection","2-Acetylaminofluorene","Alanine Transaminase","Alkaline Phosphatase","Animals","Apoptosis","Aspartate Aminotransferases","Carcinoma, Hepatocellular","Caspase 3","Cytochromes c","Diethylnitrosamine","Disease Models, Animal","Flavonoids","Hepatocytes","Liver","Liver Neoplasms","Male","Membrane Potential, Mitochondrial","Mitochondria","Mitochondrial Swelling","Organ Size","Rats","Rats, Sprague-Dawley","Reactive Oxygen Species","alpha-Fetoproteins"],"mesh_terms":["Alanine Transaminase","Alkaline Phosphatase","alpha-Fetoproteins","Animals","Aspartate Aminotransferases","Diethylnitrosamine","Disease Models, Animal","Flavonoids","Carcinoma, Hepatocellular","Liver","Liver Neoplasms","Male","Mitochondria","Mitochondrial Swelling","Organ Size","2-Acetylaminofluorene","Rats, Sprague-Dawley","Apoptosis","Reactive Oxygen Species","Hepatocytes","Cytochromes c","Rats","Membrane Potential, Mitochondrial","Caspase 3"],"keywords":["Myricetin","myr","Apoptosis","Mitochondrion","Cytochrome c","Hepatocyte","Reactive oxygen species","Hepatocellular carcinoma","Cancer research","Liver cancer","Biology","Pharmacology","Chemistry","Medicine","Biochemistry","Flavonoid","In vitro","Antioxidant","Gene"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-12T11:01:36.070656Z","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":[]}