Hypoxia-inducible factor 1 protects neurons from Sarm1-mediated neurodegeneration

The sterile alpha and TIR motif-containing 1 (Sarm1) NAD⁺ hydrolase drives neurodegeneration, but how Sarm1 activity is regulated remains poorly defined. Using CRISPR-Cas9 screening, we found that loss of Vhl suppressed Sarm1-mediated cellular degeneration. Vhl promotes O₂-dependent constitutive ubiquitination and degradation of hypoxia-inducible factor 1 (HIF-1), but during hypoxia, HIF-1 is stabilized and regulates gene expression. We observed neuroprotection in primary neurons after depletion of Vhl or other factors required for HIF-1 degradation, and expression of a non-ubiquitinated HIF-1 variant led to strong blockade of axon degeneration in primary mouse neurons and Drosophila. Neuroprotection required HIF-1 DNA binding and prolonged expression and resulted in broad gene expression changes. Unexpectedly, stabilized HIF-1 prevented NAD⁺ loss driven by Sarm1 activation in neurons, despite NAD+ hydrolase activity being intrinsic to the Sarm1 TIR domain. Our work argues that hypoxia inhibits Sarm1 activity through HIF-1-driven transcriptional changes, rendering neurons in a hypoxic state less sensitive to Sarm1-mediated neurodegeneration.