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<p>HIF1α-driven lung adenocarcinoma, a fatal subtype of non-small cell lung cancer with 1.8 million deaths per year worldwide, highlights the need for new targeted treatments. The present work investigated the tumor-suppressing potential of the isolated and biochemically characterized flavonoids on HIF1α-driven lung adenocarcinoma through combined oncoinformatic profiling, molecular simulations, and CRISPR/Cas9-mediated HIF1α-knockout validation. Oncoinformatic profiling revealed HIF1α overexpression and promoter methylation as top predictors for poor prognosis. The pharmacokinetic and pharmacodynamic screening identified myricetin and robinetin as lead flavonoids with potent HIF1α binding by molecular docking (-9.33 to -8.98&#xa0;kcal/mol) and long-term stability in long-duration molecular dynamics simulations (200&#xa0;ns), supported by structural dynamics (RMSD, RMSF, Rg, SASA, MolSA, and PSA) and binding free energy (MM/GBSA) parameters. A twenty five-gene cluster linked HIF1α to flavonoid metabolism, suggesting synergistic therapeutic targets. CRISPR-engineered HIF1α-deficient NCI-H1694 (gene effect score-negative) cells were less flavonoid-sensitive (IC<sub>50</sub>/IC<sub>80</sub> 34.5/68.2&#xa0;μM) than HIF1α-proficient gene effect score-positive cell lines (NCI-H1299, NCI-H526, NCI-H1355; IC<sub>50</sub> 12.4–18.7&#xa0;μM), validating HIF1α-dependent activity. These results place myricetin and robinetin in the category of precision drugs for HIF1α vulnerability, with potential applications for flavonoid-based therapies in lung adenocarcinoma. Through a combination of computational design, biosynthesis, and functional validation, this research presents a paradigm for next-generation, HIF1α-targeted oncology therapies.</p> Graphical Abstract <p>Illustration of the sequential-but-integrated <i>in vitro</i> and <i>in silico</i> approaches of dose-optimization of selective novel natural flavonoids</p> <p></p>

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Extraction, Characterization, and Dual-Phase Dosage Optimization of Selective Tumor-suppressing Flavonoids for Inhibiting Cellular Proliferation in CRISPR/Cas9-Mediated HIF1α-Knockout Lung Adenocarcinoma: Integrated In Vitro and In Silico Analysis

  • 期刊论文

  • 发表日期：

    2025年8月20日

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  • Salauddin Al Azad,
  • Tamanna Naznin Shetu,
  • A K M Helal Morshed,
  • Tahira Panah,
  • Sabiha Sultana,
  • Rasel Ahmed,
  • Sabbir Hasan,
  • Nawfal Hasan Siam,
  • Tasfia Islam,
  • Fawzia Tabassum,
  • Sabrina Afrin,
  • Nazia Nazrul Nafsi,
  • Asma Khanam Nafia,
  • Pritthy Sarker,
  • Safa Faria,
  • Fahmida Haque Riya

摘要

HIF1α-driven lung adenocarcinoma, a fatal subtype of non-small cell lung cancer with 1.8 million deaths per year worldwide, highlights the need for new targeted treatments. The present work investigated the tumor-suppressing potential of the isolated and biochemically characterized flavonoids on HIF1α-driven lung adenocarcinoma through combined oncoinformatic profiling, molecular simulations, and CRISPR/Cas9-mediated HIF1α-knockout validation. Oncoinformatic profiling revealed HIF1α overexpression and promoter methylation as top predictors for poor prognosis. The pharmacokinetic and pharmacodynamic screening identified myricetin and robinetin as lead flavonoids with potent HIF1α binding by molecular docking (-9.33 to -8.98 kcal/mol) and long-term stability in long-duration molecular dynamics simulations (200 ns), supported by structural dynamics (RMSD, RMSF, Rg, SASA, MolSA, and PSA) and binding free energy (MM/GBSA) parameters. A twenty five-gene cluster linked HIF1α to flavonoid metabolism, suggesting synergistic therapeutic targets. CRISPR-engineered HIF1α-deficient NCI-H1694 (gene effect score-negative) cells were less flavonoid-sensitive (IC50/IC80 34.5/68.2 μM) than HIF1α-proficient gene effect score-positive cell lines (NCI-H1299, NCI-H526, NCI-H1355; IC50 12.4–18.7 μM), validating HIF1α-dependent activity. These results place myricetin and robinetin in the category of precision drugs for HIF1α vulnerability, with potential applications for flavonoid-based therapies in lung adenocarcinoma. Through a combination of computational design, biosynthesis, and functional validation, this research presents a paradigm for next-generation, HIF1α-targeted oncology therapies.

Graphical Abstract

Illustration of the sequential-but-integrated in vitro and in silico approaches of dose-optimization of selective novel natural flavonoids