{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:17:03Z","timestamp":1790741823062,"version":"4.1.0"},"reference-count":57,"publisher":"American Society for Clinical Investigation","issue":"2","license":[{"start":{"date-parts":[[2024,1,23]],"date-time":"2024-01-23T00:00:00Z","timestamp":1705968000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81830015,82230012,82070829"],"award-info":[{"award-number":["81830015,82230012,82070829"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100012166","name":"National Key R&D Program of China","doi-asserted-by":"crossref","award":["2018YFA0800600"],"award-info":[{"award-number":["2018YFA0800600"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Natural Science Foundation of Shanghai","award":["22ZR1418800"],"award-info":[{"award-number":["22ZR1418800"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,23]]},"abstract":"<jats:p>\n                    Drug-induced liver injury (DILI), especially acetaminophen overdose, is the leading cause of acute liver failure. Pregnane X receptor (PXR) is a nuclear receptor and the master regulator of drug metabolism. Aberrant activation of PXR plays a pathogenic role in the acetaminophen hepatotoxicity. Here, we aimed to examine the S-nitrosylation of PXR (SNO-PXR) in response to acetaminophen. We found that PXR was S-nitrosylated in hepatocytes and the mouse livers after exposure to acetaminophen or S-nitrosoglutathione (GSNO). Mass spectrometry and site-directed mutagenesis identified the cysteine 307 as the primary residue for S-nitrosylation (SNO) modification. In hepatocytes, SNO suppressed both agonist-induced (rifampicin and SR12813) and constitutively active PXR (VP-PXR, a human PXR fused to the minimal transactivator domain of the herpes virus transcription factor VP16) activations. Furthermore, in acetaminophen-overdosed mouse livers, PXR protein was decreased at the centrilobular regions overlapping with increased SNO. In\n                    <jats:italic>\n                      PXR\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    mice, replenishing the livers with the SNO-deficient PXR significantly aggravated hepatic necrosis, increased HMGB1 release, and exacerbated liver injury and inflammation. Particularly, we demonstrated that S-nitrosoglutathione reductase (GSNOR) inhibitor N6022 promoted hepatoprotection by increasing the levels of SNO-PXR. In conclusion, PXR is posttranslationally modified by SNO in hepatocytes in response to acetaminophen. This modification mitigated the acetaminophen-induced PXR hyperactivity. It may serve as a target for therapeutical intervention.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.172632","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T12:00:36Z","timestamp":1701345636000},"source":"Crossref","is-referenced-by-count":14,"title":["S-nitrosylation attenuates pregnane X receptor hyperactivity and acetaminophen-induced liver injury"],"prefix":"10.1172","volume":"9","author":[{"given":"Qi","family":"Cui","sequence":"first","affiliation":[{"name":"Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China."},{"name":"School of Basic Medical Sciences, Xi\u2019an Jiaotong University, Xi\u2019an, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Jiang","sequence":"additional","affiliation":[{"name":"Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China."},{"name":"School of Basic Medical Sciences, Xi\u2019an Jiaotong 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