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LHPP Attenuates Lipid Dysfunction of Uveal Melanoma by Relieving the Histidine Phosphorylation of ACO2

Zhi Yang1,2, Liang Ma1,2, Yidian Fu1,2

  • 1State Key Laboratory of Eye Health, Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.

Research (Washington, D.C.)
|September 24, 2025
PubMed

Insights

Histidine phosphorylation is linked to poor uveal melanoma prognosis. The enzyme LHPP reverses this modification, restoring mitochondrial function and inhibiting lipid synthesis, offering a potential therapeutic strategy for this ocular tumor.

Area of Science:

  • Biochemistry
  • Oncology
  • Ophthalmology

Background:

  • Histidine phosphorylation is a crucial posttranslational modification.
  • Dysfunctional lipid metabolism is linked to uveal melanoma (UM), a deadly adult ocular tumor.
  • The role of histidine phosphorylation in UM pathogenesis is largely unknown.

Purpose of the Study:

  • To investigate the role of histidine phosphorylation in uveal melanoma.
  • To explore the therapeutic potential of targeting histidine phosphorylation in UM.
  • To elucidate the molecular mechanisms underlying histidine phosphorylation in UM.

Main Methods:

  • Analysis of histidine phosphorylation levels in UM patient samples.
  • Investigating the enzymatic activity and localization of phosphohistidine (pHis) phosphatases, specifically LHPP.
  • Utilizing cell-based assays and mouse models to study the effects of LHPP on UM and lipid metabolism.
  • Mass spectrometry to identify protein targets of histidine phosphorylation and dephosphorylation.

Main Results:

  • Increased histidine phosphorylation correlates with poor prognosis in uveal melanoma.
  • LHPP, a pHis phosphatase, exhibits mitochondrial localization and therapeutic effects by reversing histidine phosphorylation.
  • LHPP dephosphorylates mitochondrial aconitase ACO2 at H73, restoring its activity and TCA cycle function.
  • Reduced citrate accumulation due to LHPP activity attenuates lipid synthesis, impacting UM progression.
  • Genetic ablation of LHPP in mice leads to abnormal lipid metabolism in the eye.

Conclusions:

  • Aberrant histidine phosphorylation promotes uveal melanoma progression.
  • LHPP acts as a tumor suppressor by restoring mitochondrial metabolism and reducing lipid synthesis.
  • Targeting histidine phosphorylation, particularly via LHPP, represents a promising therapeutic avenue for uveal melanoma.
  • This study provides novel insights into the metabolic roles of pHis modification in ocular diseases.

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