Epothilone B stabilizes microtubules via Tau to protect retinal ganglion cells and promote axon regeneration.

BACKGROUND: As the structural framework and conduit for axonal material transport, microtubule stability plays a crucial role in the repair of optic nerve injury. Tau maintains the integrity of these transport tracks by promoting microtubule bundling. However, injury-induced aberrant phosphorylation of Tau markedly impairs its microtubule-binding capacity, leading to microtubule disassembly and eventual neurodegeneration. This study investigated Tau-mediated regulation of microtubule homeostasis and explored its potential application in axonal repair and regeneration following optic nerve injury. METHODS: Using molecular docking and molecular dynamics simulations, we identified epothilone B (EpoB) as a microtubule-stabilizing compound and systematically characterized its interaction mechanisms with the tubulin-Tau complex. Two mouse retinal ganglion cell (RGC) axonal injury models, retinal ischemia-reperfusion (I/R) and optic nerve crush (ONC), were established to evaluate neuroprotective effects through adeno-associated virus-mCherry axonal labeling and electron microscopy. Comprehensive assessments integrating anterograde and retrograde axon tracing (CTB/Fluoro-gold) and visual electrophysiology elucidated the regulatory mechanisms of microtubule stabilization on axonal protection and regeneration. RESULTS: Molecular dynamics simulations revealed that EpoB stabilizes the binding interface between Tau and tubulin via hydrogen bonding and hydrophobic interactions, significantly reducing the binding free energy (ΔG(bind) difference of 15.8 kcal mol(− 1)) and enhancing the affinity between tubulin and Tau. In mouse models of RGC injury, retinal I/R and ONC, EpoB treatment significantly inhibited abnormal phosphorylation at Tau Thr231/Ser262/Ser396 sites and reduced the formation of retraction bulbs by more than 50%. It preserved the ordered microtubule structure within axonal retraction bulbs, enhanced anterograde and retrograde transport functions, maintained long-distance axonal projections, and protected RGCs. Furthermore, EpoB can maintain microtubule stability in growth cones, producing an additive improvement in promoting axonal regeneration of optic nerves when combined with PTEN knockdown. CONCLUSION: This study reveals a novel mechanism by which EpoB stabilizes microtubules via Tau and presents a strategy for promoting axonal repair and regeneration by stabilizing microtubules, providing a new perspective for treating diseases associated with optic nerve injury. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-026-02733-2.