{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:28:44Z","timestamp":1786516124766,"version":"build-2736575974"},"reference-count":46,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,8,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Diabetic steatohepatitis, now clinically framed within metabolic dysfunction\u2010associated steatohepatitis (MASH), features progressive disruption of hepatic microarchitecture alongside sterile inflammatory microdomains. Farnesoid X receptor (FXR) activity is restrained by acetylation and p300 recruitment. CD38\u2010driven NAD\n                    <jats:sup>+<\/jats:sup>\n                    depletion also limits SIRT1 activity, suggesting a linked regulatory axis. We tested whether combined CD38 inhibition and FXR activation reprogram acetylation\u2010dependent FXR complexes, restore hepatic tissue organization, and suppress NLRP3 inflammasome signaling. Male rats with diabetic steatohepatitis received vehicle, CD38 inhibition, FXR activation, or the combination. Outcomes included steatohepatitis activity score, fibrosis burden, lipid and glucose homeostasis, insulin resistance indices, and NLRP3 pathway activity, including caspase\u20101, IL\u20101\u03b2, and IL\u201018. Diabetic steatohepatitis induced hepatic architectural disorganization, dyslipidemia, insulin resistance, and activation of the NLRP3\u2010caspase\u20101\u2010IL\u20101\u03b2\/IL\u201018 axis. Single\u2010pathway modulation improved these abnormalities, whereas combined CD38 inhibition and FXR activation produced the greatest reductions in steatohepatitis activity score and the most consistent normalization of metabolic indices with no evidence of overt toxicity. Diabetic steatohepatitis tissue exhibited FXR hyperacetylation and increased FXR association with p300 and NLRP3; combination therapy reduced FXR acetylation and weakened both interactions. Pharmacologic disruption of SIRT1 or FXR partially reversed metabolic, inflammatory, and molecular effects, while selective inflammasome inhibition lowered inflammasome outputs without altering the CD38\u2010NAD\n                    <jats:sup>+<\/jats:sup>\n                    \u2010SIRT1 node. Together, coordinated restoration of NAD\n                    <jats:sup>+<\/jats:sup>\n                    \/SIRT1 activity and FXR signaling reprograms FXR acetylation, disengages inflammasome signaling, and improves hepatic tissue organization in diabetic steatohepatitis.\n                  <\/jats:p>","DOI":"10.1096\/fj.202602105r","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T15:33:16Z","timestamp":1785857596000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CD38 Inhibition Enhances FXR Signaling in Male Rats With Diabetic Steatohepatitis Through SIRT1\u2010Dependent Suppression of NLRP3"],"prefix":"10.1096","volume":"40","author":[{"given":"Rabab S.","family":"Hamad","sequence":"first","affiliation":[{"name":"Biological Sciences Department, College of Science King Faisal University  Al Ahsa Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5070-7851","authenticated-orcid":false,"given":"Sameh","family":"Saber","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy Delta University for Science and Technology  Gamasa Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdel\u2010Moneim Hafez","family":"Abdel\u2010Moneim","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine Qassim University  Buraidah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam S.","family":"Alharbi","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine Qassim University  Buraidah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Almansour","sequence":"additional","affiliation":[{"name":"Department of Medicine, College of Medicine Qassim University  Buraidah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norah Suliman","family":"Alsoqih","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, College of Medicine Qassim University  Buraidah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa M.","family":"Khodeir","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Medicine Qassim University  Buraidah Saudi Arabia"},{"name":"Department of Pathology, Faculty of Medicine Cairo University  Cairo Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manal Mohamed","family":"Hatem","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology, College of Medicine Qassim University  Buraidah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"El\u2010Sayed","sequence":"additional","affiliation":[{"name":"Faculty of Medicine Horus University  New Damietta Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad Y.","family":"Rezk","sequence":"additional","affiliation":[{"name":"Department of Physiology, College of Medicine Qassim University  Buraidah Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheren F. M.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine Sohag University  Sohag Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed A. M.","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science Imam Mohammad Ibn Saud Islamic University (IMSIU)  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anis Ahmad","family":"Chaudhary","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science Imam Mohammad Ibn Saud Islamic University (IMSIU)  Riyadh Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attalla F.","family":"El\u2010kott","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science King Khalid University  Abha Saudi Arabia"},{"name":"Department of Zoology, Faculty of Science Damanhour University  Damanhour Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esmael M.","family":"Alyami","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science King Khalid University  Abha Saudi 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