2. Academic Validation
  3. A neuron subtype-specific role of MEK-ERK signaling in axon survival via transcriptional regulation of Nmnat2

A neuron subtype-specific role of MEK-ERK signaling in axon survival via transcriptional regulation of Nmnat2

  • Cell Rep. 2026 Feb 24;45(2):116931. doi: 10.1016/j.celrep.2026.116931.
Wenkai Yue 1,  Zhebin Wu 1,  Kai Zhang 1,  Wenjing Long 1,  Jihong Cui 2,  Ang Li 3,  Yanshan Fang 4
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
  • 3 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou 510632, China; Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong Key Laboratory of Non-human Primate Research, GHM Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China. Electronic address: [email protected].
  • 4 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
PMID: 41619208 DOI: 10.1016/j.celrep.2026.116931
Abstract

Axon degeneration is a key pathological feature in neural injuries and neurological disorders. MEK1/2 inhibitors (MEKis) are used in Cancer therapy but can cause peripheral nerve lesions. Paradoxically, they are being considered for neurodegenerative diseases. Here, we show that MEK inhibition enhances, whereas its activation protects against, injury- or chemotherapy-induced axon degeneration in mouse DRG neurons. Mechanistically, the Raf-MEK-ERK cascade upregulates the critical axon survival factor Nmnat2 via ERK phosphorylation-dependent transcription. The MEKi trametinib decreases Nmnat2 expression and induces axon degeneration in DRG neurons, which is rescued by Nmnat2 overexpression. In contrast, cortical and spinal neurons maintain Nmnat2 transcription via CREB, independent of MEK-ERK, and are resistant to trametinib. Our findings demonstrate a neuron subtype-specific mechanism whereby MEK-ERK promotes axon stability through Nmnat2 upregulation. This context-dependent axon survival paradigm helps explain the vulnerability of PNS neurons to MEKi-induced axon degeneration, highlighting Nmnat2 as a potential target to counteract MEKi-associated neuropathy.

Keywords

CIPN; CP: Molecular biology; CP: neuroscience; MAPK pathway; MEK inhibitor; Nmnat2; axon degeneration; trametinib; transcriptional regulation.

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