Iranian Journal of Basic Medical Sciences

Iranian Journal of Basic Medical Sciences

Naftidrofuryl alleviates LPS-mediated inflammatory-oxidative and fibrotic successions in a rat model of acute lung injury: An emerging mechanistic role of PPARα/SIRT1/ATF3 axis

Articles in Press

Document Type : Original Article

Authors
Manar M. Tabaa 1
Eman S. Hamada 1
Eman Rashad 2
Sally E. Abouresha 3
1 Pharmacology & Environmental Toxicology, Environmental Studies & Research Institute (ESRI), University of Sadat City, Sadat City 32897, Menoufia, Egypt
2 Cytology and Histology Department, Faculty of Veterinary Medicine, Cairo University, Egypt
3 Pharmacology & Toxicology Department, Faculty of Pharmacy, Tanta University, Tanta 31111, Egypt
10.22038/ijbms.2026.93207.20098
Abstract
Objective(s): Platelet-released serotonin (5-HT) is linked to lung inflammatory injury. Simultaneously, PPARα activation increases SIRT1 activity, thereby regulating inflammatory damage in acute lung injury (ALI). Also, ATF3 can prevent ALI-related inflammation and oxidative injury. However, the relationship between 5-HT and PPARα/SIRT1/ATF3 in ALI remains ambiguous. Hence, exploring the impact of naftidrofuryl (NAFT), a 5-HT2A antagonist, on LPS-induced ALI in rats, particularly in combination with dexamethasone (DEXA), may be valuable, given the involvement of the PPARα/SIRT1/ATF3 axis. Our investigation identified targets and pathways associated with the therapeutic benefits of NAFT using network pharmacology and molecular docking.
Materials and Methods: For in vivo validation, 64 rats were allocated to 8 groups. Lung W/D ratio and MPO activity were quantified. The BALF HO-1, MDA, TAC, PPARα, SIRT1, ATF3, TNF-α, IL-6, and IL-1β levels were analyzed. Further, expressions of JAK2, STAT3, HMGB1, AMPK, Nrf2, and MyD88 were assessed. Lung tissues were examined histologically and immunohistochemically to determine NF-κB, caspase-3, and TGF-β1 expression.
Results: Network pharmacology disclosed 176 intersecting targets between “NAFT-ALI” and “DEXA-ALI” with various KEGG pathways. Docking confirmed a strong affinity between NAFT and SIRT1, HMGB1, AMPK, and ATF3. Experimentally, NAFT inhibited JAK2/STAT3 and elevated PPARα levels. PPARα lowered TGFβ1-promoted fibroblastic proliferation and stimulated SIRT1-mediated HMGB1 deacetylation. Hence, HMGB1 repression prevented caspase-3-provoked apoptosis and enhanced the antioxidant role of AMPK/Nrf2/HO-1. Jointly, AMPK released ATF3, which consequently stopped TLR4/MyD88/NF-kB-associated inflammatory cascade.
Conclusion: NAFT may alleviate inflammation, oxidative stress, apoptosis, and fibrosis in ALI by activating the PPARα/SIRT1/ATF3 pathway. Moreover, NAFT may enhance DEXA treatment, particularly in resistant ALI patients.
Keywords
Acute lung injury
ATF3
Lipopolysaccharides
Naftidrofuryl
PPAR alpha
SIRT1
Subjects
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Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 07 October 2026