Scholarlink

Background <p>In Alport nephropathy, tightly interconnected fibrotic, inflammatory, and oxidative cascades are activated, elevating reactive oxygen species (ROS) that intensify renal injury. The broad activation of stress-responsive and profibrotic pathways further induces disease progression and limits the efficacy of monotherapies.</p> Results <p>We performed structure-based docking and long-timescale molecular dynamics simulations to identify mechanistically complementary agents, enabling the assessment of ligand stability, specificity, and suitability for selecting an effective drug combination. These analyses revealed stable histone deacetylase binding by ivaltinostat and sustained JNK1 engagement by genistein, supporting their selection as complementary antifibrotic and anti-inflammatory agents. To translate these insights, we engineered PEG-TK-C18/DSPE-PEG-maleimide nanomixed micelles that are functionalized with the proximal-tubule-targeting peptide (KKEEE)₃K-C (PPCK), co-loading both drugs, to yield PPCK + IG. Thioketal linkages conferred ROS-responsive cleavage and controlled release, while (KKEEE)₃K-C enhanced proximal tubule targeting. In <i>Col4a3</i><sup>–/–</sup> mice, PPCK + IG exhibited selective renal accumulation, oxidative activation, and robust suppression of fibrotic (α-SMA, fibronectin, and p-Smad2/3) and inflammatory markers (p-JNK, IL-6, and MCP-1), as well as downstream ERK attenuation, significantly improving renal function.</p> Conclusions <p>The findings of our study demonstrate precision nanotherapy that exploits pathological oxidative stress for targeted delivery and the coordinated modulation of epigenetic and MAPK pathways, offering a promising strategy for Alport nephropathy and other chronic kidney diseases.</p> Graphical abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Multiscale molecular modeling–directed ROS-responsive nanotherapy for dual-axis regulation of fibrotic and inflammatory signaling in alport nephropathy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月12日

查看全文
  • Hong Sang Choi,
  • Aravindkumar Sundaram,
  • Arathy Vasukutty,
  • Ansuja Pulikkal Mathew,
  • Padmanaban Sathiyamoorthy,
  • In Jin Kim,
  • Sang Heon Suh,
  • Chang Seong Kim,
  • Seong Kwon Ma,
  • Soo Wan Kim,
  • In-Kyu Park,
  • Eun Hui Bae

摘要

Background

In Alport nephropathy, tightly interconnected fibrotic, inflammatory, and oxidative cascades are activated, elevating reactive oxygen species (ROS) that intensify renal injury. The broad activation of stress-responsive and profibrotic pathways further induces disease progression and limits the efficacy of monotherapies.

Results

We performed structure-based docking and long-timescale molecular dynamics simulations to identify mechanistically complementary agents, enabling the assessment of ligand stability, specificity, and suitability for selecting an effective drug combination. These analyses revealed stable histone deacetylase binding by ivaltinostat and sustained JNK1 engagement by genistein, supporting their selection as complementary antifibrotic and anti-inflammatory agents. To translate these insights, we engineered PEG-TK-C18/DSPE-PEG-maleimide nanomixed micelles that are functionalized with the proximal-tubule-targeting peptide (KKEEE)₃K-C (PPCK), co-loading both drugs, to yield PPCK + IG. Thioketal linkages conferred ROS-responsive cleavage and controlled release, while (KKEEE)₃K-C enhanced proximal tubule targeting. In Col4a3–/– mice, PPCK + IG exhibited selective renal accumulation, oxidative activation, and robust suppression of fibrotic (α-SMA, fibronectin, and p-Smad2/3) and inflammatory markers (p-JNK, IL-6, and MCP-1), as well as downstream ERK attenuation, significantly improving renal function.

Conclusions

The findings of our study demonstrate precision nanotherapy that exploits pathological oxidative stress for targeted delivery and the coordinated modulation of epigenetic and MAPK pathways, offering a promising strategy for Alport nephropathy and other chronic kidney diseases.

Graphical abstract