2. Academic Validation
  3. Penfluridol targets acid sphingomyelinase to inhibit TNF signaling and is therapeutic against inflammatory autoimmune diseases

Penfluridol targets acid sphingomyelinase to inhibit TNF signaling and is therapeutic against inflammatory autoimmune diseases

  • Arthritis Res Ther. 2022 Jan 19;24(1):27. doi: 10.1186/s13075-021-02713-6.
Yue-Hong Chen 1 2,  Rong-Han Liu 1,  Ya-Zhou Cui 1,  Aubryanna Hettinghouse 1,  Wen-Yu Fu 1,  Lei Zhang 1,  Chen Zhang 1,  Chuan-Ju Liu 3 4
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, New York University Grossman School of Medicine, Rm 1608, HJD, 301 East 17th Street, New York, NY, 10003, USA.
  • 2 Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, 610000, China.
  • 3 Department of Orthopaedic Surgery, New York University Grossman School of Medicine, Rm 1608, HJD, 301 East 17th Street, New York, NY, 10003, USA. [email protected].
  • 4 Department of Cell Biology, New York University Grossman School of Medicine, New York, NY, 10016, USA. [email protected].
PMID: 35045889 DOI: 10.1186/s13075-021-02713-6
Abstract

Background: Penfluridol, 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.

Methods: Various 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.

Results: Penfluridol 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.

Conclusion: This 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.

Keywords

Acid sphingomyelinase; Arthritis; Colitis; Penfluridol; Tumor necrosis factor α, NF-κB.

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