The tubulin code in acute ischemic stroke: post-translational reprogramming of the neuronal cytoskeleton and implications for phase-specific neuroprotection

Acute ischemic stroke initiates a rapid convergence of excitotoxicity, calcium overload, oxidative stress, neuroinflammation, and energetic failure. Although reperfusion therapies remain central to acute care, they do not directly address the structural failure of injured neuronal networks. This narrative review examines the neuronal microtubule cytoskeleton as an active regulatory platform whose function is governed by the tubulin code: tubulin isotype composition and post-translational modifications. The review integrates evidence that ischemia alters alpha-tubulin K40 acetylation, detyrosination, delta-2 tubulin accumulation, and polyglutamylation, while also examining emerging roles for palmitoylation, lactylation, and glycylation-related PTM cross-talk. Particular emphasis is placed on the HDAC6-alpha-tubulin acetylation axis, MIF-AIF parthanatos signaling, vasohibin-dependent detyrosination, CCP1-dependent control of polyglutamylation, TUBA4A-GSK3beta-Tau scaffolding, beta-tubulin isotype effects on whole-lattice behavior, and lactylation-mediated repair. Together, these pathways support a phase-specific model in which early cytoprotection preserves transport-competent microtubules, whereas later recovery requires adaptive cytoskeletal remodeling and neuroplasticity.