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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\u2013expressing 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\u2013 but not K8-K393R\u2013induced filament disruption and cell death. Importantly, parthenolide normalized K14-R125C\u2013mediated 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.<\/jats:p>","DOI":"10.1172\/jci.insight.166314","type":"journal-article","created":{"date-parts":[[2023,7,23]],"date-time":"2023-07-23T14:01:07Z","timestamp":1690120867000},"source":"Crossref","is-referenced-by-count":4,"title":["Deacetylation via SIRT2 prevents keratin-mutation-associated injury and keratin aggregation"],"prefix":"10.1172","volume":"8","author":[{"given":"Jingyuan","family":"Sun","sequence":"first","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey, USA."},{"name":"Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, PR China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1837-2753","authenticated-orcid":true,"given":"Pei","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3624-4800","authenticated-orcid":true,"given":"Honglian","family":"Gui","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai, PR China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4551-1691","authenticated-orcid":true,"given":"Laure","family":"Ritti\u00e9","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David B.","family":"Lombard","sequence":"additional","affiliation":[{"name":"Sylvester Comprehensive Cancer Center, and Department of Pathology & Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrin","family":"Rietscher","sequence":"additional","affiliation":[{"name":"Division of Cell and Developmental Biology, Institute of Biology, Leipzig University, Leipzig, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas M.","family":"Magin","sequence":"additional","affiliation":[{"name":"Division of Cell and Developmental Biology, Institute of Biology, Leipzig University, Leipzig, Germany."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai, PR China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Liu","sequence":"additional","affiliation":[{"name":"Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, PR China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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