Ferulic acid mitigates 3-Nitropropionic acid-induced Huntington’s disease via modulation of Nrf2/HO-1, TLR4/NF-κB, and SIRT1/p53 signaling pathways

Abdelgawad, Mohamed A., Gendy, Abdallah M., Zaghlool, Sameh S., Elesawy, Wessam H., Ragab, Mai F., Kotb El-Sayed, Mohamed I., El-Haddad, Alaadin E., Mohamed, Hussein S., Alsalahat, Izzeddin and Essa, Marwa A. 2025. Ferulic acid mitigates 3-Nitropropionic acid-induced Huntington’s disease via modulation of Nrf2/HO-1, TLR4/NF-κB, and SIRT1/p53 signaling pathways. Frontiers in Pharmacology 16 , 1678724. 10.3389/fphar.2025.1678724

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Abstract

Background: Ferulic acid (FA) is a natural phenolic compound that has demonstrated effectiveness against Huntington’s disease (HD). However, its exact mechanism remains unclear. Therefore, the current study aims to investigate FA’s potential mechanism of action against 3-nitropropionic acid (3NP)-induced HD. Methods: Adult male Wistar albino rats were administered FA orally (100 mg/kg) for 3 weeks, and 3NP (10 mg/kg) was intraperitoneally administered during the last 2 weeks to induce HD. Behavioral performance was assessed using the open field and hanging wire tests. Striatal tissue was analyzed using ELISA, qRT-PCR, Western blotting, histopathology, and immunohistochemistry. Results: Administration of 3NP led to weight loss, neurobehavioral deficits, oxidative damage, apoptotic cell death, and neuroinflammation. FA treatment mitigated these pathological changes by activating Nrf2/HO-1 signaling, a critical player in cellular redox balance. This beneficial effect was mirrored in restoring TAC levels and suppressing MDA. Moreover, FA suppressed TLR4/NF-κB inflammatory signaling, thereby reducing TNF-α and IL-1β levels. In addition, the anti-apoptotic properties of FA were confirmed by modulating SIRT1/p53 signaling, leading to Bcl-2 enhancement and caspase-3 downsizing. Furthermore, FA enhanced neuronal survival and plasticity confirmed by neurotrophic BDNF elevation. Histopathological and immunohistochemical analyses confirmed improved neuronal survival and reduced gliosis following FA treatment. Conclusion: The current research demonstrates that FA exhibits potent neuroprotective effects in experimental HD by modifying Nrf2/HO-1, TLR4/NF-κB, and SIRT1/p53 signaling pathways. These findings provide new mechanistic insights into FA’s potential role in managing HD.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Pharmacy
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	Frontiers Media
Date of Acceptance:	22 September 2025
Last Modified:	22 Oct 2025 13:15
URI:	https://orca.cardiff.ac.uk/id/eprint/181840

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