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<p>Leukaemia remains a critical haematologic malignancy, where current therapies offer limited efficacy and are frequently associated with significant toxicity. Epigenetic dysregulation, particularly aberrant histone deacetylase (HDAC) activity, promotes uncontrolled proliferation and suppression of apoptosis in leukaemic cells, with HDAC7 identified as a central driver of disease progression. Daidzein, a natural isoflavonoid from <i>Macrotyloma uniflorum</i>, represents a promising plant-derived HDAC inhibitor. This study evaluated daidzein’s anti-leukaemic potential using integrated computational, in vitro, and in vivo approaches.&#xa0;Molecular docking and dynamics simulations confirmed stable HDAC7 binding with a binding affinity of −7.6 kcalmol⁻¹, comparable to vorinostat (SAHA; −6.7 kcalmol⁻¹). Daidzein significantly inhibited HL-60 cell viability (IC₅₀ = 19.6 µM) and HDAC activity (IC₅₀ = 3.4 µM), induced apoptosis and G₀/G₁ arrest, and modulated key epigenetic markers by downregulating HDAC7 and enhancing H3K27 acetylation. <i>In vivo,</i> daidzein markedly reduced blast cell burden in blood and bone marrow and alleviated leukaemia-associated hepatic and splenic pathology. HDAC7 suppression was further verified by immunohistochemistry in spleen and liver tissues. Moreover, peripheral blood mononuclear cell profiling showed enhancement of T cells and myeloid cells with concurrent reductions in B cells and macrophages, suggesting immunomodulatory potential.The demonstrated anti-leukaemic and immunomodulatory effects support further investigation toward potential clinical use.</p> Graphical abstract <p>Daidzein as HDAC inhibitors: <b>1)</b> a thorough <i>in silico</i> analysis ranging from Pharmacophore modelling to molecular dynamics simulations; <b>2)</b> Phytochemical analysis of Daidzein through HPLC identification and quantification and structural analysis of isolated daidzein from <i>Macrotyloma uniflorum</i> confirmed by <sup>1</sup>H,<sup>12</sup>C NMR, <b>3)</b> an <i>in vitro</i> assessment of daidzein: Apoptosis induction, Cell cycle arrest, Inhibition of HDAC7 in HL-60 cell lines, and leukemia cell inhibition; and <b>4)</b> an <i>in vivo</i> investigation of daidzein: spleen and liver histopathology, PBMC isolation, spleen and liver histopathology, and HDAC7 suppression via immunohistochemistry resulting in fewer blast cells in leukemia.</p> <p></p>

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Epigenetic Inhibition of HDAC7 by Daidzein isolated from Macrotyloma uniflorum: A potential therapeutic approach in leukemia in silico, in-vitro and in-vivo

  • 期刊论文

  • 发表日期：

    2026年1月12日

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  • Amber Rizwan,
  • Yeshfeen Sherwani,
  • Zaid Siddiqui,
  • Humaira Farooqi,
  • Bibhu Prasad Panda,
  • Mairaj Ahmed Ansari,
  • Asma Khanday

摘要

Leukaemia remains a critical haematologic malignancy, where current therapies offer limited efficacy and are frequently associated with significant toxicity. Epigenetic dysregulation, particularly aberrant histone deacetylase (HDAC) activity, promotes uncontrolled proliferation and suppression of apoptosis in leukaemic cells, with HDAC7 identified as a central driver of disease progression. Daidzein, a natural isoflavonoid from Macrotyloma uniflorum, represents a promising plant-derived HDAC inhibitor. This study evaluated daidzein’s anti-leukaemic potential using integrated computational, in vitro, and in vivo approaches. Molecular docking and dynamics simulations confirmed stable HDAC7 binding with a binding affinity of −7.6 kcalmol⁻¹, comparable to vorinostat (SAHA; −6.7 kcalmol⁻¹). Daidzein significantly inhibited HL-60 cell viability (IC₅₀ = 19.6 µM) and HDAC activity (IC₅₀ = 3.4 µM), induced apoptosis and G₀/G₁ arrest, and modulated key epigenetic markers by downregulating HDAC7 and enhancing H3K27 acetylation. In vivo, daidzein markedly reduced blast cell burden in blood and bone marrow and alleviated leukaemia-associated hepatic and splenic pathology. HDAC7 suppression was further verified by immunohistochemistry in spleen and liver tissues. Moreover, peripheral blood mononuclear cell profiling showed enhancement of T cells and myeloid cells with concurrent reductions in B cells and macrophages, suggesting immunomodulatory potential.The demonstrated anti-leukaemic and immunomodulatory effects support further investigation toward potential clinical use.

Graphical abstract

Daidzein as HDAC inhibitors: 1) a thorough in silico analysis ranging from Pharmacophore modelling to molecular dynamics simulations; 2) Phytochemical analysis of Daidzein through HPLC identification and quantification and structural analysis of isolated daidzein from Macrotyloma uniflorum confirmed by 1H,12C NMR, 3) an in vitro assessment of daidzein: Apoptosis induction, Cell cycle arrest, Inhibition of HDAC7 in HL-60 cell lines, and leukemia cell inhibition; and 4) an in vivo investigation of daidzein: spleen and liver histopathology, PBMC isolation, spleen and liver histopathology, and HDAC7 suppression via immunohistochemistry resulting in fewer blast cells in leukemia.