{"doi":"10.1002/advs.202200750","title":"Aberrant Cholesterol Metabolism and Wnt/<i>β</i>‐Catenin Signaling Coalesce via Frizzled5 in Supporting Cancer Growth","abstract":"Frizzled (Fzd) proteins are Wnt receptors and play essential roles in development, homeostasis, and oncogenesis. How Wnt/Fzd signaling is coupled to physiological regulation remains unknown. Cholesterol is reported as a signaling molecule regulating morphogen such as Hedgehog signaling. Despite the elusiveness of the in-depth mechanism, it is well-established that pancreatic cancer specially requires abnormal cholesterol metabolism levels for growth. In this study, it is unexpectedly found that among ten Fzds, Fzd5 has a unique capacity to bind cholesterol specifically through its conserved extracellular linker region. Cholesterol-binding enables Fzd5 palmitoylation, which is indispensable for receptor maturation and trafficking to the plasma membrane. In Wnt-addicted pancreatic ductal adenocarcinoma (PDAC), cholesterol stimulates tumor growth via Fzd5-mediated Wnt/β-catenin signaling. A natural oxysterol, 25-hydroxylsterol competes with cholesterol and inhibits Fzd5 maturation and Wnt signaling, thereby alleviating PDAC growth. This cholesterol-receptor interaction and ensuing receptor lipidation uncover a novel mechanism by which Fzd5 acts as a cholesterol sensor and pivotal connection coupling lipid metabolism to morphogen signaling. These findings further suggest that cholesterol-targeting may provide new therapeutic opportunities for treating Wnt-dependent cancers.","journal":"Advanced Science","year":2022,"id":235399,"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":81,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.95,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":854038,"name":"Jiahui Lin","orcid":null,"position":1,"is_corresponding":false},{"id":854039,"name":"Zhongqiu Pang","orcid":null,"position":2,"is_corresponding":false},{"id":539374,"name":"Hui Zhang","orcid":"0000-0002-6331-6876","position":3,"is_corresponding":false},{"id":53369,"name":"Yinuo Wang","orcid":null,"position":4,"is_corresponding":false},{"id":853282,"name":"Lanjing Ma","orcid":"0009-0009-9690-2060","position":5,"is_corresponding":false},{"id":839752,"name":"Haijiao Zhang","orcid":"0000-0002-0749-9866","position":6,"is_corresponding":false},{"id":853283,"name":"Xi Zhang","orcid":"0000-0002-0067-860X","position":7,"is_corresponding":false},{"id":404078,"name":"Maorong Chen","orcid":"0000-0003-3744-8864","position":8,"is_corresponding":false},{"id":386079,"name":"Xinjun Zhang","orcid":"0000-0003-2409-4104","position":9,"is_corresponding":false},{"id":853284,"name":"Chao Zhao","orcid":"0000-0003-3569-2732","position":10,"is_corresponding":false},{"id":260598,"name":"Jun Qi","orcid":"0000-0002-1461-3356","position":11,"is_corresponding":false},{"id":853285,"name":"Liu Cao","orcid":"0000-0001-6471-1993","position":12,"is_corresponding":false},{"id":4907,"name":"Min Wang","orcid":"0000-0002-3420-4031","position":13,"is_corresponding":false},{"id":263200,"name":"Xi He","orcid":"0000-0002-8093-7981","position":14,"is_corresponding":false},{"id":577673,"name":"Ren Sheng","orcid":"0000-0002-2293-8986","position":15,"is_corresponding":false},{"id":853281,"name":"Shaoqin Zheng","orcid":"0000-0002-3027-7305","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-19T00:21:48.116752Z","pmid":"35975457","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":[]}