Heat shock protein 90β lactylation acts as a metabolic switch to drive cerebrovascular apoptosis under heat stress
- Cell Rep. 2026 May 26;45(5):117317. doi: 10.1016/j.celrep.2026.117317.
- 1. Department of Otolaryngology Head & Neck Surgery/Deep Underground Space Medical Center, West China Hospital, Sichuan University, No. 37 Guoxuexiang, Chengdu, China; West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, No. 17, Section 3, Renmin South Road, Chengdu, China.
- 2. Department of Otolaryngology Head & Neck Surgery/Deep Underground Space Medical Center, West China Hospital, Sichuan University, No. 37 Guoxuexiang, Chengdu, China.
- 3. Department of Otolaryngology Head & Neck Surgery/Deep Underground Space Medical Center, West China Hospital, Sichuan University, No. 37 Guoxuexiang, Chengdu, China; Jinping Deep Underground Frontier Science and Dark Matter Key Laboratory of Sichuan Province, Liangshan, China; State Key Laboratory of Intelligent Construction and Healthy Operation and Maintenance of Deep Underground Engineering, Sichuan University, No.24, South Section 1, 1st Ring Road, Chengdu, China.
- 4. Department of Emergency Medicine, Emergency Medical Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
- 5. Department of Emergency Medicine, Emergency Medical Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, China. Electronic address: [email protected].
- 6. Department of Otolaryngology Head & Neck Surgery/Deep Underground Space Medical Center, West China Hospital, Sichuan University, No. 37 Guoxuexiang, Chengdu, China; Jinping Deep Underground Frontier Science and Dark Matter Key Laboratory of Sichuan Province, Liangshan, China; State Key Laboratory of Intelligent Construction and Healthy Operation and Maintenance of Deep Underground Engineering, Sichuan University, No.24, South Section 1, 1st Ring Road, Chengdu, China. Electronic address: [email protected].
- 7. Department of Otolaryngology Head & Neck Surgery/Deep Underground Space Medical Center, West China Hospital, Sichuan University, No. 37 Guoxuexiang, Chengdu, China; Jinping Deep Underground Frontier Science and Dark Matter Key Laboratory of Sichuan Province, Liangshan, China; State Key Laboratory of Intelligent Construction and Healthy Operation and Maintenance of Deep Underground Engineering, Sichuan University, No.24, South Section 1, 1st Ring Road, Chengdu, China. Electronic address: [email protected].
Lysine lactylation (Kla) is a metabolite-sensing post-translational modification that bridges cellular metabolism to protein function. Here, we discover that heat stress triggers anaerobic glycolysis and lactate accumulation in brain microvascular endothelial cells. We find that plasma lactate inversely correlates with Glasgow Coma Scale scores in heat stroke patients and predicts poor outcomes. Mechanistically, AARS1 catalyzes the transfer of lactate to HSP90β at lysine 275 (K275). Critically, the lactylation of HSP90β disrupts its interaction with apoptotic protease-activating factor 1 (APAF-1). This modification compromises the protective function of HSP90β, liberating APAF-1 to activate the mitochondrial Apoptosis pathway, resulting in blood-brain barrier (BBB) injury. Functional validation reveals that decreasing lactate production or inhibiting AARS1 confers protection. These findings establish HSP90β K275 lactylation as a metabolic switch that modulates protective mechanisms during heat stress-induced cerebrovascular injury. Collectively, our study provides insights into heat stress pathogenesis and identifies potential therapeutic targets for heat-related brain damage.
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Research Areas: Cancer
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