ALDOA Promotes Glycolysis and NLRP3/GSDMD Pyroptosis to Accelerate ALS Progression

  • Ann Clin Transl Neurol. 2026 Mar 24. doi: 10.1002/acn3.70372.
Kaixin Yan  1 ,  Yan Jiang  1 ,  Yuxuan Yong  1 ,  Tianshuo Zhang  2 ,  Niannian Zhang  3 ,  Qianqian Zeng  3 ,  Xue Gong  2 ,  Li Meng  3 ,  Fangfang Bi  1  2 ,  Yongmin Liu  2
Affiliations
  • 1. Department of Neurology, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
  • 2. Department of Neurology, Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, China.
  • 3. Department of Neurology, Xiangya Hospital Central South University, Changsha, China.
PMID: 41876403 DOI: 10.1002/acn3.70372
Abstract

Objective: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration. Glycolytic dysregulation is implicated in disease progression, yet the underlying mechanisms remain unclear. This study investigates how Aldolase A (ALDOA) drives ALS progression through glycolysis-mediated motor neuron Pyroptosis.

Methods: In vivo, tamoxifen-induced TDP-43 cKO mice were assessed for motor function (rotarod/suspension tests), motor cortex L-lactic acid, and ALDOA/NLRP3/GSDMD expression. The ALDOA inhibitor Aldometanib was administered. In vitro, TDP-43 KO NSC34 cells were used to measure viability, glucose uptake, and L-lactic acid.

Results: ALS model mice exhibited significant motor deficits, progressive weight loss, and reduced survival. Their motor cortex showed elevated ALDOA expression, L-lactic acid accumulation, and NLRP3/GSDMD inflammasome activation. Aldometanib treatment suppressed glycolysis, prolonged survival, and slowed disease progression by inhibiting NLRP3/GSDMD-mediated Pyroptosis. In vitro, TDP-43-deficient NSC34 cells displayed increased ALDOA levels, enhanced glycolytic flux, NLRP3/GSDMD pathway activation, and impaired proliferation.

Conclusion: We show that ALDOA-mediated glycolytic dysregulation activates the NLRP3/GSDMD inflammasome, leading to Pyroptosis in motor neurons. Pharmacological inhibition of ALDOA alleviates glycolytic dysregulation and extends survival, identifying ALDOA as a potential therapeutic target.

Keywords
ALDOA; ALS; Aldometanib; glycolysis; pyroptosis.
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