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.