ArticleArthritis research & therapy2022
Penfluridol targets acid sphingomyelinase to inhibit TNF signaling and is therapeutic against inflammatory autoimmune diseases.
Article in Arthritis research & therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 13 citations in OpenAlex.
- Penfluridol synergizes with colistin to reverse colistin resistance in Gram-negative bacilli.Scientific reports · 2025Article
- The Key Role and Mechanism of Oxidative Stress in Hypertrophic Cardiomyopathy: A Systematic Exploration Based on Multi-Omics Analysis and Experimental Validation.Antioxidants (Basel, Switzerland) · 2025Article
- Suberosin attenuates rheumatoid arthritis by repolarizing macrophages and inhibiting synovitis via the JAK/STAT signaling pathway.Arthritis research & therapy · 2025Article
- Macrophage-derived mir-100-5p orchestrates synovial proliferation and inflammation in rheumatoid arthritis through mTOR signaling.Journal of nanobiotechnology · 2024Article
- Tau deficiency inhibits classically activated macrophage polarization and protects against collagen-induced arthritis in mice.Arthritis research & therapy · 2023Article
- Penfluroidol Attenuates the Imbalance of the Inflammatory Response by Repressing the Activation of the NLRP3 Inflammasome and Reduces Oxidative Stress via the Nrf2/HO-1 Signaling Pathway in LPS-Induced Macrophages.Mediators of inflammation · 2023Article
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundPenfluridol, isolated from an FDA-approved small-molecule drug library as an inhibitor of tumor necrosis factor α (TNFα)-stimulated NF-κB activation, is clinically used to treat chronic schizophrenia and related disorders. This study is aimed to investigate the therapeutic effect of penfluridol on TNFα-stimulated inflammatory autoimmune diseases, particularly inflammatory arthritis.
methodsVarious in vitro studies to confirm the inhibitory effect of penfluridol on TNFα-induced NF-κB activity in bone marrow-derived macrophages or Raw 264.7 macrophage cell line. In vivo studies assessed the therapeutic effects of penfluridol in various disease models, including TNFα transgenic mice, collagen-induced arthritis, DSS-induced colitis, and TNBS-induced colitis. Identification and characterization of the binding of penfluridol to acid sphingomyelinase using bioinformatics and drug affinity responsive target stability assay. Acid sphingomyelinase activity assays to reveal penfluridol-mediated inhibition of acid sphingomyelinase activity. siRNA knockdown experiments to illustrate the dependence of penfluridol's anti-TNF activity on acid sphingomyelinase.
resultsPenfluridol effectively inhibited TNFα-induced NF-κB activation in vitro and alleviated the severity of arthritis and colitis in vivo. Mechanistic studies revealed that penfluridol bound to acid sphingomyelinase and inhibited its activation. In addition, knockdown of acid sphingomyelinase largely abolished the inhibitory effects of penfluridol on TNFα-induced inflammatory cytokine production. Furthermore, penfluridol suppressed the differentiation of spleen naive CD4+T cells to TH1 and TH17 and inhibited M1 macrophage polarization.
conclusionThis study provides the rationale for the possible innovative use of penfluridol as a newly identified small-molecule drug for TNFα-driven diseases, such as inflammatory arthritis and colitis.
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