Micheliolide and ACT001 as Covalent Modulators of Inflammation-Redox-Metabolism Networks in CNS Disorders: An Evidence-Stratified Review of Mechanisms and Translational Challenges.

Micheliolide (MCL), a guaianolide sesquiterpene lactone bearing an α-methylene-γ-lactone Michael acceptor pharmacophore, and its orally bioavailable prodrug ACT001 have been studied in a growing range of central nervous system (CNS) disorders, including traumatic brain injury, Parkinson's disease, neuropathic pain, neuromyelitis optica spectrum disorder, and glioblastoma. These compounds act beyond classical pathway inhibition (that is, blockade of any single linear signalling cascade in isolation) by modulating interconnected inflammatory, redox, and metabolic signalling modules. This review integrates preclinical evidence across CNS disease models and proposes a unified three-axis framework-encompassing innate immune-inflammatory regulation, redox homeostasis, and metabolism-associated signal integration-to organise mechanistic findings, stratify evidence by direct CNS validation status, and identify translational gaps. This review is based on a structured search of PubMed and Web of Science for publications on micheliolide, DMAMCL, or ACT001 in central nervous system disorders, and the diseases are discussed in the sequence in which the supporting evidence is presented below. The inflammatory axis (NF-κB/NLRP3/TLR4/MD2/STAT3) is the best-supported CNS-relevant mechanism, with convergent evidence across traumatic brain injury, Parkinson's disease, neuropathic pain, and glioblastoma, including direct binding to the TLR4 co-receptor MD2 and IKKβ. Redox modulation (KEAP1/NRF2) remains plausible but rests primarily on peripheral models, awaiting CNS validation. The metabolism-associated axis (PKM2, GAPDH, MDK/c-Myc) is an innovative but incompletely validated frontier, with GAPDH Cys247 covalent engagement in glioblastoma as the strongest direct CNS evidence. We propose a disease-stratified model-neurodegeneration as inflammation-dominant, acute brain injury as inflammation-metabolism coupled, autoimmune and pain conditions as glial-lineage-expanded, and brain tumours as multi-axis dysregulated-requiring experimental validation. Although glioblastoma is the most translationally advanced indication for this chemotype, the shared neuroinflammatory, redox, and metabolic mechanisms engaged by MCL/ACT001 provide a strong rationale for their evaluation across non-malignant CNS disorders. MCL and ACT001 represent a promising covalent scaffold for modulating interconnected CNS networks, with glioblastoma as the most translationally advanced indication. Priorities include quantitative CNS pharmacokinetics, long-term safety of covalent pharmacology in post-mitotic neurons, and validation of metabolic-redox coupling in brain-resident cells via chemoproteomic and single-cell approaches.