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Background <p>Biologic therapies targeting TNF-α in inflammatory and autoimmune diseases underscore its central role in pathological inflammation. Epigenetic mechanisms are increasingly recognized as critical modulators of disease-associated gene expression, and advancing epigenetic-based therapeutics requires deeper insight into the transcriptional networks governing inflammatory responses. Here, we investigate the epigenetic regulation of inflammation-induced <i>TNF-α</i> transcription and identify lead compounds that suppress TNF-α expression in human macrophages.</p> Methods and results <p>A small-molecule epigenetic inhibitor screen comprising 152 compounds was performed to assess their effects on LPS-induced <i>TNF-α</i> transcription in THP-1 monocyte-derived macrophages. <i>TNF-α</i> mRNA and protein levels were quantified using qRT-PCR and ELISA, respectively. The screen identified 20 potent inhibitors of <i>TNF-α</i> expression, representing six major classes of epigenetic regulators: HATs, BRDs, HDACs, HDMs, PRMT1, and PLK1. Protein-protein interaction network analysis revealed extensive crosstalk between these targets and key inflammatory signaling pathways, including NF-κB and MAPK. Follow-up validation of the top 10 candidates demonstrated dose-dependent suppression of TNF-α at both transcriptional and protein levels. These compounds also exhibited broad anti-inflammatory activity, suppressing <i>IL-1β</i>, <i>IL-6</i>, <i>IL-8</i>, <i>IL-17A</i>, and <i>CCL2</i> expression, and showed cross-species efficacy in human (THP-1) and mouse (RAW264.7) macrophages. NF-κB reporter assays further indicated that their inhibitory effects are mediated, at least in part, through blockade of NF-κB activation.</p> Conclusions <p>This study identifies a regulatory network of epigenetic modifiers controlling TNF-α transcription and reveals conserved mechanisms governing inflammatory gene expression. The validated lead compounds possess potent anti-inflammatory properties and hold strong potential for therapeutic repurposing as modulators of TNF-α-driven inflammatory diseases.</p>

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A comprehensive analysis of epigenetic mechanisms regulating inflammation-induced TNF-α gene expression by small-molecule inhibitor screening

  • 期刊论文

  • 发表日期：

    2026年2月3日

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  • Komal Paresh Walvekar,
  • Sai Balaji Andugulapati,
  • Sabarinadh Chilaka

摘要

Background

Biologic therapies targeting TNF-α in inflammatory and autoimmune diseases underscore its central role in pathological inflammation. Epigenetic mechanisms are increasingly recognized as critical modulators of disease-associated gene expression, and advancing epigenetic-based therapeutics requires deeper insight into the transcriptional networks governing inflammatory responses. Here, we investigate the epigenetic regulation of inflammation-induced TNF-α transcription and identify lead compounds that suppress TNF-α expression in human macrophages.

Methods and results

A small-molecule epigenetic inhibitor screen comprising 152 compounds was performed to assess their effects on LPS-induced TNF-α transcription in THP-1 monocyte-derived macrophages. TNF-α mRNA and protein levels were quantified using qRT-PCR and ELISA, respectively. The screen identified 20 potent inhibitors of TNF-α expression, representing six major classes of epigenetic regulators: HATs, BRDs, HDACs, HDMs, PRMT1, and PLK1. Protein-protein interaction network analysis revealed extensive crosstalk between these targets and key inflammatory signaling pathways, including NF-κB and MAPK. Follow-up validation of the top 10 candidates demonstrated dose-dependent suppression of TNF-α at both transcriptional and protein levels. These compounds also exhibited broad anti-inflammatory activity, suppressing IL-1β, IL-6, IL-8, IL-17A, and CCL2 expression, and showed cross-species efficacy in human (THP-1) and mouse (RAW264.7) macrophages. NF-κB reporter assays further indicated that their inhibitory effects are mediated, at least in part, through blockade of NF-κB activation.

Conclusions

This study identifies a regulatory network of epigenetic modifiers controlling TNF-α transcription and reveals conserved mechanisms governing inflammatory gene expression. The validated lead compounds possess potent anti-inflammatory properties and hold strong potential for therapeutic repurposing as modulators of TNF-α-driven inflammatory diseases.