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<p>Nephrotoxicity poses a significant clinical challenge, contributing to renal complications and increased mortality, thus necessitating novel therapeutics with superior efficacy and safety. Our study addresses this need by evaluating flavone derivatives as potential modulators of p38-MAPK to tackle both inflammation and renal damage, using cell-based assays, cytotoxicity profiling, molecular docking, and ADME-T profiling. Notably, 3,6-dihydroxyflavone (3,6-DHF) and 3,7-dihydroxyflavone (3,7-DHF) demonstrated a significant reduction in KIM-1 mRNA expression in CCl<sub>4</sub>-induced damaged renal epithelial cells while exhibiting no cytotoxic effects on Vero cells at therapeutic doses. Protein slot blot analyses revealed alteration in expression of total p38-MAPK, with 3,6-DHF exhibiting the strongest inhibitory effect. On the other hand, both DHFs effectively quenched reactive oxygen and nitrogen species from phagocytes, underscoring their anti-inflammatory properties. Molecular docking showed high binding affinity for p38-MAPK, with values of − 6.8 kcal/mol for 3,6-DHF and − 6.05 kcal/mol for 3,7-DHF, while ADME-T profiling revealed compliance with the Lipinski rule, good gastrointestinal absorption, and low toxicity risk. The findings suggest the promising anti-inflammatory and renoprotective properties of 3,6-DHF and 3,7-DHF, offering potential benefits for the treatment of nephropathies and associated inflammation. Future directions involve in vivo validation using nephrotoxicity models and preclinical optimization of these compounds for potential clinical application in treating renal disorders.</p> Graphical Abstract <p></p>

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Dihydroxyflavones as potential therapeutic agents against inflammation and renal injury via p38 MAP kinase inhibition: an in silico and experimental study

  • 期刊论文

  • 发表日期：

    2026年5月26日

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  • Farwa Naqvi,
  • Almas Jabeen,
  • Muhammad Shafiq,
  • Shaheen Faizi,
  • Zaheer Ul-Haq

摘要

Nephrotoxicity poses a significant clinical challenge, contributing to renal complications and increased mortality, thus necessitating novel therapeutics with superior efficacy and safety. Our study addresses this need by evaluating flavone derivatives as potential modulators of p38-MAPK to tackle both inflammation and renal damage, using cell-based assays, cytotoxicity profiling, molecular docking, and ADME-T profiling. Notably, 3,6-dihydroxyflavone (3,6-DHF) and 3,7-dihydroxyflavone (3,7-DHF) demonstrated a significant reduction in KIM-1 mRNA expression in CCl4-induced damaged renal epithelial cells while exhibiting no cytotoxic effects on Vero cells at therapeutic doses. Protein slot blot analyses revealed alteration in expression of total p38-MAPK, with 3,6-DHF exhibiting the strongest inhibitory effect. On the other hand, both DHFs effectively quenched reactive oxygen and nitrogen species from phagocytes, underscoring their anti-inflammatory properties. Molecular docking showed high binding affinity for p38-MAPK, with values of − 6.8 kcal/mol for 3,6-DHF and − 6.05 kcal/mol for 3,7-DHF, while ADME-T profiling revealed compliance with the Lipinski rule, good gastrointestinal absorption, and low toxicity risk. The findings suggest the promising anti-inflammatory and renoprotective properties of 3,6-DHF and 3,7-DHF, offering potential benefits for the treatment of nephropathies and associated inflammation. Future directions involve in vivo validation using nephrotoxicity models and preclinical optimization of these compounds for potential clinical application in treating renal disorders.

Graphical Abstract