The sesquiterpene alcohol farnesol mitigates cadmium hepatotoxicity by attenuating oxidative stress and NF-κB/NLRP3 inflammasome axis and upregulating PPARγ in rats

Alruhaimi, Reem S ORCID: https://orcid.org/0000-0003-3746-8582, Hassanein, Emad H M ORCID: https://orcid.org/0000-0003-4865-2342, Alnasser, Sulaiman M ORCID: https://orcid.org/0000-0001-8678-5029, Alzoghaibi, Mohammed A ORCID: https://orcid.org/0000-0002-9036-4187, Abd El-Ghafar, Omnia A M ORCID: https://orcid.org/0009-0002-0578-6068, Mohammad, Mostafa K ORCID: https://orcid.org/0009-0005-2836-7378, Elbagory, Ibrahim ORCID: https://orcid.org/0000-0002-9125-0333 and Mahmoud, Ayman M ORCID: https://orcid.org/0000-0003-0279-6500 (2024) The sesquiterpene alcohol farnesol mitigates cadmium hepatotoxicity by attenuating oxidative stress and NF-κB/NLRP3 inflammasome axis and upregulating PPARγ in rats. EXCLI Journal, 23. pp. 1356-1374.

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Abstract

Farnesol (FAR) is a sesquiterpene alcohol that exists in many fruits and vegetables and possesses promising anti-inflammatory and antioxidant activities. Cadmium (Cd) is an environmental pollutant known for its serious health effects. Liver injury associated with oxidative stress is a hazardous consequence of exposure to Cd. This study evaluated the effect of FAR on Cd-induced oxidative stress, inflammation, and hepatocyte injury, pinpointing the involvement of NF-κB/NLRP3 inflammasome axis, TGF-β/Smad3 signaling and PPARγ. FAR was supplemented for 14 days and rats received Cd on day 7. Elevated serum transaminases, ALP and LDH, decreased albumin, and multiple histopathological alterations were observed in Cd-administered rats. Cd increased liver MDA and NO, decreased GSH and antioxidant enzymes, and upregulated NF-κB p65, IL-6, TNF-α, iNOS, NLRP3, ASC, caspase-1, IL-1β, and cleaved caspase-3. TGF-β, Smad3 phosphorylation and α-SMA were upregulated, and collagen deposition was increased in Cd-administered rats. FAR ameliorated liver injury markers and tissue alterations, attenuated oxidative stress, suppressed NF-κB/NLRP3 inflammasome axis and TGF-β/Smad3 signaling, and enhanced antioxidants. In addition, FAR downregulated caspase-3 and pro-inflammatory cytokines and increased liver PPARγ in Cd-administered rats. In silico, FAR showed affinity to bind ASC and NLRP3 PYD domains, TGF-β, and PPARγ. In conclusion, FAR protects the liver against Cd toxicity by suppressing oxidative stress, inflammatory response and cell death, effects linked to modulation of NF-κB/NLRP3 inflammasome axis, TGF-β/Smad3 signaling and PPARγ.