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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\u2010mediated motor neuron pyroptosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In vivo, tamoxifen\u2010induced TDP\u201043 cKO mice were assessed for motor function (rotarod\/suspension tests), motor cortex L\u2010lactic acid, and ALDOA\/NLRP3\/GSDMD expression. The ALDOA inhibitor Aldometanib was administered. In\u00a0vitro, TDP\u201043 KO NSC34 cells were used to measure viability, glucose uptake, and L\u2010lactic acid.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>ALS model mice exhibited significant motor deficits, progressive weight loss, and reduced survival. Their motor cortex showed elevated ALDOA expression, L\u2010lactic acid accumulation, and NLRP3\/GSDMD inflammasome activation. Aldometanib treatment suppressed glycolysis, prolonged survival, and slowed disease progression by inhibiting NLRP3\/GSDMD\u2010mediated pyroptosis. In\u00a0vitro, TDP\u201043\u2010deficient NSC34 cells displayed increased ALDOA levels, enhanced glycolytic flux, NLRP3\/GSDMD pathway activation, and impaired proliferation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We show that ALDOA\u2010mediated 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70372","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T03:50:22Z","timestamp":1774410622000},"page":"1903-1918","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>ALDOA<\/scp>\n                    Promotes Glycolysis and\n                    <scp>NLRP3<\/scp>\n                    \/\n                    <scp>GSDMD<\/scp>\n                    Pyroptosis to Accelerate\n                    <scp>ALS<\/scp>\n                    Progression"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9430-0975","authenticated-orcid":false,"given":"Kaixin","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Neurology The Second 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