{"doi":"10.1172/jci.insight.166314","title":"Deacetylation via SIRT2 prevents keratin-mutation-associated injury and keratin aggregation","abstract":"Keratin (K) and other intermediate filament (IF) protein mutations at conserved arginines disrupt keratin filaments into aggregates and cause human epidermolysis bullosa simplex (EBS; K14-R125C) or predispose to mouse liver injury (K18-R90C). The challenge for more than 70 IF-associated diseases is the lack of clinically utilized IF-targeted therapies. We used high-throughput drug screening to identify compounds that normalized mutation-triggered keratin filament disruption. Parthenolide, a plant sesquiterpene lactone, dramatically reversed keratin filament disruption and protected cells and mice expressing K18-R90C from apoptosis. K18-R90C became hyperacetylated compared with K18-WT and treatment with parthenolide normalized K18 acetylation. Parthenolide upregulated the NAD-dependent SIRT2, and increased SIRT2-keratin association. SIRT2 knockdown or pharmacologic inhibition blocked the parthenolide effect, while site-specific Lys-to-Arg mutation of keratin acetylation sites normalized K18-R90C filaments. Treatment of K18-R90C-expressing cells and mice with nicotinamide mononucleotide had a parthenolide-like protective effect. In 2 human K18 variants that associate with human fatal drug-induced liver injury, parthenolide protected K18-D89H- but not K8-K393R-induced filament disruption and cell death. Importantly, parthenolide normalized K14-R125C-mediated filament disruption in keratinocytes and inhibited dispase-triggered keratinocyte sheet fragmentation and Fas-mediated apoptosis. Therefore, keratin acetylation may provide a novel therapeutic target for some keratin-associated diseases.","journal":"JCI Insight","year":2023,"id":375193,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":536580,"name":"Pei Li","orcid":"0000-0003-1837-2753","position":1,"is_corresponding":false},{"id":1137386,"name":"Honglian Gui","orcid":"0000-0003-3624-4800","position":2,"is_corresponding":false},{"id":1137387,"name":"Laure Rittié","orcid":"0000-0003-4551-1691","position":3,"is_corresponding":false},{"id":23524,"name":"David B. Lombard","orcid":"0000-0002-4292-0185","position":4,"is_corresponding":false},{"id":922242,"name":"Katrin Rietscher","orcid":null,"position":5,"is_corresponding":false},{"id":692874,"name":"Thomas M. Magin","orcid":"0000-0001-7016-2409","position":6,"is_corresponding":false},{"id":388397,"name":"Qing Xie","orcid":"0000-0003-2889-5670","position":7,"is_corresponding":false},{"id":339212,"name":"Li Liu","orcid":"0000-0003-2314-8756","position":8,"is_corresponding":false},{"id":32138,"name":"M. Bishr Omary","orcid":"0000-0002-8624-2347","position":9,"is_corresponding":false},{"id":1137385,"name":"Jingyuan Sun","orcid":"0000-0003-3485-0567","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T01:16:19.336238Z","pmid":"37485877","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":[]}