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<p>IgA nephropathy (IgAN) is the most common primary glomerular disease, but the mechanisms of renal injury and the role of necroptosis in IgAN remain unclear. In this exploratory study, we performed nanoparticle-based enrichment proteomics to profile low-abundance serum proteins an in-house cohort, focusing on curated necroptosis-related proteins (NRPs). By integrating bulk transcriptomic and single-cell sequencing data (scRNA-Seq), we identified key co-expression modules using weighted gene co-expression network analysis (WGCNA), gene set variation analysis (GSVA), and Mfuzz clustering, and assessed their associations with clinical indices of renal injury. Transcriptomic analysis identified necroptosis as the most significantly dysregulated PCD pathway in IgAN, with GSVA scores positively correlated with urinary protein-to-creatinine ratio, suggesting that necroptosis activity is associated with early renal injury. Proteomic profiling identified 1,627 differentially expressed proteins (DEPs; FDR &lt; 0.05, |fold change|&gt; 1.5), of which 156 were NRPs. WGCNA identified the MEbrown module as strongly associated with IgAN and Oxford T-score (the strongest pathological predictor of kidney injury). Integration of proteomic, transcriptomic, and network data identified BTK, SYK, and PLEC as key upregulated necroptosis-related proteins. scRNA-seq analysis revealed that BTK and SYK were primarily expressed in immune cells. Their expression levels showed strong inverse correlations with eGFR, and receiver operating characteristic (ROC) analysis indicated high diagnostic performance. In summary, our study demonstrates marked dysregulation of the necroptosis pathway in IgAN, while acknowledging that the elevated BTK and SYK reflect both canonical immune activation and concurrent necroptosis-related renal injury. These molecules correlate with disease severity and renal function decline, supporting their potential as exploratory serum biomarkers and candidate therapeutic targets. Our findings provide mechanistic insights linking immune dysregulation and programmed cell death in IgAN, and support further development of non-invasive diagnostic and therapeutic strategies in larger, independent cohorts.</p> Graphical abstract <p></p>

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Protein corona-based low-abundance proteomics identifies BTK and SYK as biomarkers associated with disease severity in IgA nephropathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月10日

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  • Huiyi Zeng,
  • Wei Zhang,
  • Mingjun Ye,
  • Shouping Zhu,
  • Chen Yun,
  • Yue Peng,
  • Jingjing Dong,
  • Chengcheng Liu,
  • Shaodong Luan,
  • Hualin Ma,
  • Bing Yan,
  • Lianghong Yin,
  • Yong Dai,
  • Donge Tang

摘要

IgA nephropathy (IgAN) is the most common primary glomerular disease, but the mechanisms of renal injury and the role of necroptosis in IgAN remain unclear. In this exploratory study, we performed nanoparticle-based enrichment proteomics to profile low-abundance serum proteins an in-house cohort, focusing on curated necroptosis-related proteins (NRPs). By integrating bulk transcriptomic and single-cell sequencing data (scRNA-Seq), we identified key co-expression modules using weighted gene co-expression network analysis (WGCNA), gene set variation analysis (GSVA), and Mfuzz clustering, and assessed their associations with clinical indices of renal injury. Transcriptomic analysis identified necroptosis as the most significantly dysregulated PCD pathway in IgAN, with GSVA scores positively correlated with urinary protein-to-creatinine ratio, suggesting that necroptosis activity is associated with early renal injury. Proteomic profiling identified 1,627 differentially expressed proteins (DEPs; FDR < 0.05, |fold change|> 1.5), of which 156 were NRPs. WGCNA identified the MEbrown module as strongly associated with IgAN and Oxford T-score (the strongest pathological predictor of kidney injury). Integration of proteomic, transcriptomic, and network data identified BTK, SYK, and PLEC as key upregulated necroptosis-related proteins. scRNA-seq analysis revealed that BTK and SYK were primarily expressed in immune cells. Their expression levels showed strong inverse correlations with eGFR, and receiver operating characteristic (ROC) analysis indicated high diagnostic performance. In summary, our study demonstrates marked dysregulation of the necroptosis pathway in IgAN, while acknowledging that the elevated BTK and SYK reflect both canonical immune activation and concurrent necroptosis-related renal injury. These molecules correlate with disease severity and renal function decline, supporting their potential as exploratory serum biomarkers and candidate therapeutic targets. Our findings provide mechanistic insights linking immune dysregulation and programmed cell death in IgAN, and support further development of non-invasive diagnostic and therapeutic strategies in larger, independent cohorts.

Graphical abstract