Glyoxylic acid-induced calcium oxalate crystal deposition drives nephrotoxicity via SPHK1-mediated ferroptosis: Insights from untargeted lipidomics

  • Chem Biol Interact. 2026 Jul 1:434:112105. doi: 10.1016/j.cbi.2026.112105.
Meng Shu  1 ,  Yiying Jia  1 ,  Bangyu Zou  1 ,  Shuwei Zhang  1 ,  Zhaoxin Ying  1 ,  Xinling Xiang  1 ,  Dongxiang Zhang  1 ,  Ziyu Fang  2 ,  Yonghan Peng  3 ,  Xiaofeng Gao  4
Affiliations
  • 1. Department of Urology, Changhai Hospital of Shanghai, Naval Medical University, Shanghai, 200433, China; Shanghai Key Laboratory of Cell Engineering, Shanghai, 200433, China.
  • 2. Department of Urology, Changhai Hospital of Shanghai, Naval Medical University, Shanghai, 200433, China; Shanghai Key Laboratory of Cell Engineering, Shanghai, 200433, China. Electronic address: [email protected].
  • 3. Department of Urology, Changhai Hospital of Shanghai, Naval Medical University, Shanghai, 200433, China; Shanghai Key Laboratory of Cell Engineering, Shanghai, 200433, China. Electronic address: [email protected].
  • 4. Department of Urology, Changhai Hospital of Shanghai, Naval Medical University, Shanghai, 200433, China; Shanghai Key Laboratory of Cell Engineering, Shanghai, 200433, China. Electronic address: [email protected].
PMID: 42044864 DOI: 10.1016/j.cbi.2026.112105
Abstract

Glyoxylic acid (GA), an endogenous precursor to oxalate, is a known nephrotoxicant and a key driving factor in chemical-induced kidney injury and the pathogenesis of nephrolithiasis, primarily through inducing renal calcium oxalate (CaOx) crystal deposition. However, the precise lipid metabolic mechanisms underlying its nephrotoxic effects remain unclear. This study employed untargeted lipidomics to investigate renal lipid alterations and their role in GA-induced nephrotoxicity and CaOx crystal deposition. In an in vivo model, C57BL/6 mice were exposed to GA (100 mg/kg/day, 7 days), resulting in significant renal CaOx deposition, tubular injury, inflammation, and impaired renal function (elevated serum creatinine and urea nitrogen), confirming successful induction of nephrotoxicity. Lipidomics profiling identified 658 significantly dysregulated renal lipids (319 upregulated, 339 downregulated), primarily within glycerophospholipid and glycerolipid metabolism. Enrichment analyses (Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA)) revealed pronounced disruptions in sphingolipid metabolism, with a notable impact on the Ferroptosis pathway. Using an in vitro model, we treated human renal tubular (HK-2) cells with calcium oxalate monohydrate (COM; 0, 15, 30, 60 μg/cm2 for 24 h) and confirmed the upregulation of sphingosine kinase 1 (SphK1) and the activation of Ferroptosis, as evidenced by decreased Glutathione Peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) expression and increased acyl-CoA synthetase long-chain family member 4 (ACSL4) expression. Critically, pharmacological inhibition of SphK1 with PF543 (at 0.5, 1.0, 2.0 μmol/L in vitro) or its lentiviral knockdown attenuated Ferroptosis, improved cell viability. Furthermore, in vivo administration of PF543 (1.0 mg/kg, 2.5 mg/kg) reduced renal CaOx deposition and mitigated GA-induced renal injury. Our findings unveil profound renal lipid dysregulation in GA-induced nephrotoxicity and establish the SPHK1-ferroptosis axis as a pivotal mechanistic link and a promising therapeutic target for counteracting this chemical-induced renal damage.

Keywords
Calcium oxalate; Ferroptosis; Glyoxylic acid; Lipidomics; Nephrotoxicity; SPHK1.
Products