Directional Modulation of the Integrated Stress Response in Neurodegeneration: A Systematic Review of eIF2B Activators, PERK-Pathway Agents, and ISR Prolongers

<b>Background and Objectives</b>: The integrated stress response (ISR) is a convergent node in neurodegeneration. We systematically mapped open-access mammalian in vivo evidence for synthetic ISR modulators, comparing efficacy signals, biomarker engagement, and safety across mechanisms and disease classes. <b>Methods</b>: Following PRISMA 2020, we searched PubMed (MEDLINE), Embase, and Scopus from inception to 22 September 2025. Inclusion required mammalian neurodegeneration models; synthetic ISR modulators (eIF2B activators, PERK inhibitors or activators, GADD34-PP1 ISR prolongers); prespecified outcomes; and full open access. Extracted data included model, dose and route, outcomes, translational biomarkers (ATF4, phosphorylated eIF2α), and safety. <b>Results</b>: Twelve studies met the criteria across tauopathies and Alzheimer's disease (n = 5), prion disease (n = 1), amyotrophic lateral sclerosis and Huntington's disease (n = 3), hereditary neuropathies (n = 2), demyelination (n = 1), and aging (n = 1). Among interpretable in vivo entries, 10 of 11 reported benefit in at least one domain. By class, eIF2B activation with ISRIB was positive in three of four studies, with one null Alzheimer's hAPP-J20 study; PERK inhibition was positive in all three studies; ISR prolongation with Sephin1 or IFB-088 was positive in both studies; and PERK activation was positive in both studies. Typical regimens included ISRIB 0.1-2.5 mg per kg given intraperitoneally (often two to three doses) with reduced ATF4 and phosphorylated eIF2α; oral GSK2606414 50 mg per kg twice daily for six to seven weeks, achieving brain-level exposures; continuous MK-28 delivery at approximately 1 mg per kg; and oral IFB-088 or Sephin1 given over several weeks. Safety was mechanism-linked: systemic PERK inhibition produced pancreatic and other exocrine toxicities at higher exposures, whereas ISRIB and ISR-prolonging agents were generally well-tolerated in the included reports. <b>Conclusions</b>: Directional ISR control yields consistent, context-dependent improvements in behavior, structure, or survival, with biomarker evidence of target engagement. Mechanism matching (down-tuning versus prolonging the ISR) and exposure-driven safety management are central for translation.