Dataset Information

Naringenin targets PI3K p85alpha to suppress PI3K/AKT signaling pathway and ameliorate disordered MMP-9 secretion in cigarette smoke extract-induced alveolar macrophages in vitro

ABSTRACT: Naringenin has demonstrated potential therapeutic effects against cigarette smoke-induced lung injury; however, its underlying mechanisms of regulating matrix metalloproteinase-9 (MMP-9) in alveolar macrophages remain unclear. Methods: The regulatory mechanisms of naringenin in cigarette smoke extract (CSE)-induced alveolar macrophages were investigated using proteomics, and then naringenin’s targets were further validated by western blot, molecular docking, molecular dynamics (MD) simu-lations, cellular thermal shift assay (CETSA), and enzyme activity assay. Results: The proteomics revealed that the PI3K/AKT signaling pathway might play a crucial role in naringenin’s inhibition of MMP-9. Western blot confirmed that naringenin significantly inhibited CSE-upregulated PI3K/AKT signaling pathway and reduced MMP-9 expression in MH-S cells. Notably, the PI3K activator 740Y-P reversed naringenin’s effects on MMP-9. Additionally, molecular docking, MD simulations, and CETSA identified PI3K p85alpha as the potential binding site for naringenin, and naringenin markedly inhibited CSE-induced PI3K activity. In in vitro experiments, naringenin inhibiting MMP-9 secre-tion in alveolar macrophages contributed to alleviating elastin and E-cadherin damage in alveolar epithelial cells. Furthermore, naringenin effectively suppressed CSE-induced MMP-9 secretion in primary mouse alveolar macrophages and human THP-1-differentiated macrophages. Conclusions: Our findings revealed that naringenin, a potential candidate for treating smoking-induced lung injury, directly targeted PI3K p85alpha, inhibiting PI3K activity and MMP-9 expression in CSE-induced alveolar macrophages via suppressing the PI3K/AKT signaling pathway.

ORGANISM(S): Mus Musculus

SUBMITTER: Peibo Li

PROVIDER: PXD063137 | iProX | Mon Apr 21 00:00:00 BST 2025

REPOSITORIES: iProX

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Naringenin Targets PI3K p85alpha to Suppress PI3K/AKT Signaling Pathway and Ameliorate Disordered MMP-9 Secretion in Cigarette Smoke Extract-Induced Alveolar Macrophages In Vitro.

Fan Weiyang W Xu Ziyan Z Zhong Mengli M Wu Xiao X Chen Pan P Chen Zhen Z Su Weiwei W Wu Hao H Li Peibo P

Cells 20250508 10

<h4>Background</h4>Naringenin has demonstrated potential therapeutic effects against cigarette smoke-induced lung injury; however, its underlying mechanisms of regulating matrix metalloproteinase-9 (MMP-9) in alveolar macrophages remain unclear.<h4>Methods</h4>The regulatory mechanisms of naringenin in cigarette smoke extract (CSE)-induced alveolar macrophages were investigated using proteomics, and then, naringenin's targets were further validated by Western blot, molecular docking, molecular d ...[more]

PMID: 40422181

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Project description:Dysregulated lipid metabolism is an oncogenic mechanism that leads to increased de novo fatty acid biosynthesis via elevated expression of fatty acid synthase (FASN) in cancer. FASN catalyzes biosynthesis of (C16) palmitic acid by using Acetyl CoA, malonyl CoA and NADPH as substrates. Palmitic acid and its derivatives participate as signaling lipids andinvolved in the regulation of receptor functions associated with many biological processes. and furtherThis includes contribute formation of cell structures, and all these processes which are essential for both normal and malignant cell growth and proliferation. In this study, we investigated the biological impact of FASN inhibition in B cell Non Hodgkin Lymphoma (bNHL) cells using FASN inhibitors Cerulenin and other novel agents (TVB3166, TVB3567). Inhibition of FASN resulted in a dose dependent increase in cell death and apoptosis in the bNHL and primary tumor cells. Transcriptomic and comprehensive systems biology analysis of cerulenin, TVB3166 or TVB3567 treated bNHL cells revealed conserved activation of (TNF) immune and PI3K signaling, and inhibition of cell cycle pathways as prominent responses to FASN inhibition. Cell fractionation and western blot analysis of cCerulenin treated cells showed translocation of TNF receptor adaptor proteins (TRAF2 and RIP), docking of AKT and PI3K/p110 subunits to cell membrane and activation of PI3K/AKT pathways by phosphorylation in SUDHL2 and SUDHL4 bNHL cells, while these mechanisms were constitutively active in cerulenin treated SUDHL10 bNHL cells. Disruption of lipid raft formation by methyl β cyclodextrin inhibited PI3K signaling and downregulated FASN expression in SUDHL10 cells. Subsequently, we observed that combination of FASN (cerulenin) and PI3K (Buparlisib) inhibitors resulted in synergistic cell death in bNHL cell lines and increased apoptosis accompanied with down-regulation of FASN expression in bNHL cell lines and primary cells, implicating the importance of PI3K in the regulation of lipid metabolism. Further mass spectrometric evaluation of cerulenin and Buparlisib treated DLBCL cells fed with C14C glucose, synergistically decreased the biosynthesis of palmitic acid and its derivatives compared to single agent treatments. Our conclusions from these investigations suggest that simultaneous blocking of PI3K and FASN is likely to exert stronger inhibition of lipid metabolism and enhance cell death in lymphoma.

Dataset Information

Naringenin targets PI3K p85alpha to suppress PI3K/AKT signaling pathway and ameliorate disordered MMP-9 secretion in cigarette smoke extract-induced alveolar macrophages in vitro

Publications

Naringenin Targets PI3K p85alpha to Suppress PI3K/AKT Signaling Pathway and Ameliorate Disordered MMP-9 Secretion in Cigarette Smoke Extract-Induced Alveolar Macrophages In Vitro.

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