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Here, we initially demonstrated the beneficial role of caspase-9-dependent autophagy in acute liver injury. Treatment with caspase-9 inhibitor z-LEHD-FMK in HepG2 cells, AML12 cells and C57BL\/b6N mice exacerbated CCl<jats:sub>4<\/jats:sub>-induced acute hepatocellular damage and also down-regulated autophagy markers expression levels, indicating that caspase-9 inhibition may aggravate acute liver damage by suppressing cytoprotective autophagy. CCl<jats:sub>4<\/jats:sub> was used as an acute liver injury inducer which caused oxidative stress and apoptosis through up-regulation of HIF-1\u03b1, as well as triggered hepatic inflammation and necroptosis via TLR4\/NF-\u03baB pathway. Caspase-9 Thr125 site was firstly phosphorylated by ERK1\/2 which subsequently activated the cytoprotective autophagy process to attenuate acute CCl<jats:sub>4<\/jats:sub> injury. Caspase-9 inhibition further aggravated hepatic necroptosis through NF-\u03baB expression, leading to increased pro-inflammatory mediators levels, suggesting a protective role of caspase-9-dependent autophagy in the inflammatory process as well as its possibility being a new therapeutic target for the treatment of acute liver injury.<\/jats:p>","DOI":"10.1038\/srep32447","type":"journal-article","created":{"date-parts":[[2016,9,1]],"date-time":"2016-09-01T10:34:04Z","timestamp":1472726044000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Inhibition of caspase-9 aggravates acute liver injury through suppression of cytoprotective autophagy"],"prefix":"10.1038","volume":"6","author":[{"given":"Rui","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing Fei","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily C.","family":"Liong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai Min","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moussa","family":"Youdim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man Lung","family":"Fung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwok Fai","family":"So","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George L.","family":"Tipoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,9,1]]},"reference":[{"key":"BFsrep32447_CR1","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/j.jhep.2010.11.005","volume":"54","author":"H Malhi","year":"2011","unstructured":"Malhi, H. & Kaufman, R. 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