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However, the role of protein Kcr in the pathogenesis of endotoxic shock-induced secondary cardiomyopathy is elusive. Here a classic rat model of endotoxic shock was induced by intraperitoneal lipopolysaccharide (LPS) injection. Crotonylproteomic analysis was subsequently performed on myocardial tissues to profile the Kcr modifications that occurred during endotoxic shock, and we found that the Kcr of carnitine palmitoyltransferase 1B (CPT1B) at the K321 site was significantly upregulated in LPS-treated rats. These findings were also confirmed in rat primary cardiomyocytes and H9C2 cells exposed to LPS. Furthermore, we demonstrated that the K321cr of CPT1B impaired CPT1B activity. Moreover, we found that the mutation of K321 to R prevented the mutant CPT1B protein from being crotonylated by LPS, thus alleviating LPS-induced lipid droplet deposition and mitochondrial dysfunction, as reflected by the recovery of ATP generation and mitochondrial membrane potential. Consistently, in vivo cardiac-specific overexpression of CPT1B via an AAV9 vector with a cardiomyocyte-specific promoter (cTnT) also confirmed that the K321-R mutation of CPT1B protected against endotoxic shock-induced secondary cardiomyopathy. Further liquid chromatography\u2013tandem mass spectrometry analysis revealed that the crotonyl-transferases P300 and CBP might be involved in the Kcr of CPT1B. Mechanistically, LPS led to the dissociation of CBP from CPT1B, which promoted the binding of P300 to CPT1B, thereby increasing the level of CPT1B K321cr in H9C2 cells. Taken together, the results of our study revealed the regulatory axis of CPT1B K321 cr\/CBP\/P300 in LPS-induced endotoxic shock.<\/jats:p>","DOI":"10.1038\/s12276-026-01730-2","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T10:20:21Z","timestamp":1779963621000},"page":"1674-1687","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CPT1B K321 crotonylation contributes to cardiac dysfunction in endotoxic shock"],"prefix":"10.1038","volume":"58","author":[{"given":"Ni","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang-Fan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Mei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ri","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Hang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng-Hui","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Ru","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Feng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanshan","family":"Ning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4954-5370","authenticated-orcid":false,"given":"Tie-Ning","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"1730_CR1","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1001\/jama.2016.0287","volume":"315","author":"M Singer","year":"2016","unstructured":"Singer, M. et al. 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