CD38 Inhibition Enhances FXR Signaling in Male Rats With Diabetic Steatohepatitis Through SIRT1-Dependent Suppression of NLRP3.

Authors

Rabab S Hamad, Sameh Saber, Abdel-Moneim Hafez Abdel-Moneim, Mariam S Alharbi, Omar Almansour, Norah Suliman Alsoqih, Mostafa M Khodeir, Manal Mohamed Hatem, Mohamed El-Sayed, Mohamad Y Rezk, Sheren F M Ahmed, Mohamed A M Ali, Anis Ahmad Chaudhary, Attalla F El-Kott, Esmael M Alyami, Sally Negm, Abousree T Ellethy, Elsayed A Elmorsy

Published in

FASEB journal : official publication of the Federation of American Societies for Experimental Biology. Volume 40. Issue 15. Pages e72187. Aug 15, 2026.

Abstract

Diabetic steatohepatitis, now clinically framed within metabolic dysfunction-associated 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-driven NAD⁺ depletion also limits SIRT1 activity, suggesting a linked regulatory axis. We tested whether combined CD38 inhibition and FXR activation reprogram acetylation-dependent 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-1, IL-1β, and IL-18. Diabetic steatohepatitis induced hepatic architectural disorganization, dyslipidemia, insulin resistance, and activation of the NLRP3-caspase-1-IL-1β/IL-18 axis. Single-pathway 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-NAD⁺-SIRT1 node. Together, coordinated restoration of NAD⁺/SIRT1 activity and FXR signaling reprograms FXR acetylation, disengages inflammasome signaling, and improves hepatic tissue organization in diabetic steatohepatitis.

PMID:
42550583
Bibliographic data and abstract were imported from PubMed on 04 Aug 2026.

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