2. Academic Validation
  3. Targeting ME1 rescues redox-metabolic coordination in ALS: A core effector of NRF2-directed therapy

Targeting ME1 rescues redox-metabolic coordination in ALS: A core effector of NRF2-directed therapy

  • Neuropharmacology. 2026 Aug 1:293:110940. doi: 10.1016/j.neuropharm.2026.110940.
Yifan Yang 1,  Yurong Yang 1,  Xiaofan Zhang 1,  Hao Ma 1,  Shengmin Ji 1,  Fangxia Zou 2,  Xin Yu 2,  Guangying Du 2,  Xiaoyin Zhu 3,  Jingwei Tian 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, Shandong, China.
  • 2 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, Shandong, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, 264003, Shandong, China.
  • 3 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, Shandong, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, 264003, Shandong, China. Electronic address: [email protected].
  • 4 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, Shandong, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, 264003, Shandong, China. Electronic address: [email protected].
PMID: 41903869 DOI: 10.1016/j.neuropharm.2026.110940
Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss, muscle weakness, and respiratory failure, with dysregulated energy metabolism and oxidative stress representing core pathological features. Epidemiological studies indicate geographical variations in incidence, and recent multi-omics evidence identifies a hypermetabolic state and mitochondrial dysfunction as key drivers of disease progression. The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), which regulates antioxidant response and metabolism, represents a promising therapeutic target; however, the exploration of specific activators remains insufficient. This study evaluated the efficacy and mechanism of a novel Keap1-Nrf2 Activator, MKL01351, in SOD1 G93A transgenic mice and NSC-34 motor neuron-like ALS models. Behavioral analyses demonstrated that MKL01351 significantly delayed disease onset, improved motor coordination in the rotarod and hanging tests, and extended survival. The compound alleviated oxidative stress by reducing malondialdehyde (MDA) levels and restoring the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, while also ameliorating the energy deficit by modulating glycolytic and mitochondrial functions, as confirmed by Seahorse analysis. Mechanistic investigations revealed that MKL01351 activated the NRF2 pathway, upregulating downstream targets such as NQO1 and HO-1, and specifically enhanced the expression of malic enzyme 1 (ME1). Loss-of-function experiments confirmed that ME1 knockdown abolished the protective effects, indicating that the NRF2-ME1 axis is a central hub for the synergistic regulation of metabolic and oxidative homeostasis. In conclusion, MKL01351 concurrently ameliorates oxidative stress and metabolic dysregulation via the NRF2-ME1 signaling pathway, offering a novel neuroprotective strategy for ALS treatment.

Keywords

ALS; ME1; Metabolic dysfunction; Mitochondrial function; NRF2; NRF2 activator; Oxidative stress.

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