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LncPTEC mediated homocysteine accumulation elevates oxidative stress via UBQLN1-dependent MTHFD1 ubiquitination in

Qijia Wang1,2, Tianhui Wu2,3, Peiling Li1,2

  • 1Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.

Cell Death & Disease
|July 7, 2026
PubMed

Insights

Homocysteine accumulation in kidney cells drives diabetic kidney disease (DKD) progression. A newly identified lncRNA, lncPTEC, exacerbates this by promoting oxidative stress and fibrosis, offering new therapeutic targets for DKD.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Biochemistry

Background:

  • Diabetic kidney disease (DKD) is a major cause of kidney failure.
  • Oxidative stress is a key factor in DKD, but its mechanisms are not fully understood.
  • Homocysteine (Hcy) accumulation in proximal tubular epithelial cells (PTECs) contributes to mitochondrial oxidative stress in DKD.

Purpose of the Study:

  • To investigate the role of homocysteine (Hcy) accumulation and identify novel molecular mechanisms in diabetic kidney disease (DKD).
  • To explore the function of a newly identified long non-coding RNA (lncRNA) in DKD pathogenesis.

Main Methods:

  • Single-cell RNA sequencing (scRNA-seq) was used to screen for DKD-associated lncRNAs.
  • In vitro and in vivo models were employed to study the effects of lncPTEC.
  • Mechanistic studies involved investigating the interaction between lncPTEC, SP1, MTHFD1, and UBQLN1.

Main Results:

  • lncPTEC, a DKD-associated lncRNA, was identified in PTECs.
  • Upregulated lncPTEC correlates with albuminuria in DKD patients and exacerbates mitochondrial oxidative stress, epithelial-mesenchymal transition (EMT), and renal fibrosis.
  • lncPTEC promotes Hcy accumulation by interacting with MTHFD1, leading to its ubiquitination and degradation via UBQLN1, under hyperglycemic conditions regulated by SP1.

Conclusions:

  • The lncPTEC/MTHFD1 axis plays a critical role in Hcy-mediated mitochondrial oxidative stress and DKD progression.
  • lncPTEC is a potential diagnostic biomarker and therapeutic target for DKD.
  • Understanding this pathway provides new insights into DKD pathogenesis.

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