Introduction: Mitochondrial dysfunction stands as a pivotal feature in neurodegenerative disorders, spurring the quest for targeted therapeutic interventions. This review examines Ubiquitin‐Specific Protease 30 (USP30) as a master regulator of mitophagy with therapeutic promise in Alzheimer's disease (AD) and Parkinson's disease (PD). USP30's orchestration of mitophagy pathways, encompassing PINK1‐dependent and PINK1‐independent mechanisms, forms the crux of this exploration.Method: A systematic literature search was conducted in PubMed, Scopus, and Web of Science, selecting studies that investigated USP's function, inhibitor design, or therapeutic efficacy in AD and PD. Inclusion criteria encompassed mechanistic and preclinical/clinical data, while irrelevant or duplicate references were excluded. Extracted findings were synthesized narratively.Results: USP30 modulates interactions with translocase of outer mitochondrial membrane (TOM) 20, mitochondrial E3 ubiquitin protein ligase 1 (MUL1), and Parkin, thus harmonizing mitochondrial quality control. Emerging novel USP30 inhibitors, racemic phenylalanine derivatives, N‐cyano pyrrolidine, and notably, benzosulphonamide class compounds, restore mitophagy, and reduce neurodegenerative phenotypes across diverse models with minimal off‐target effects. Modulation of other USPs also influences neurodegenerative disease pathways, offering additional therapeutic avenues.Conclusions: In highlighting the nuanced regulation of mitophagy by USP30, this work heralds a shift toward more precise and effective treatments, paving the way for a new era in the clinical management of neurodegenerative disorders.

An overactive neuroinflammatory response is often evident in the elderly and is a significant contributor to brain tissue damage following acute ischemic stroke. Such an inflammatory response is largely mediated by microglial cells and peripheral blood mononuclear cells (PBMCs). Classical anti-inflammatory agents have not proved clinically effective in mitigating the impact of ischemic stroke but have highlighted targets for new drug development, in particular excessive proinflammatory cytokine release. The immunomodulatory imide drug (IMiD) class has shown potential in reducing neuroinflammation and switching microglial phenotypic expression away from a proinflammatory to a regenerative anti-inflammatory one. 3-Monothiopomalidomide (3-MP), a new IMiD, has a brain/plasma concentration ratio of 0.5 to 0.6, an oral bioavailability of 38.5%, and a monophasic disappearance of half-life 3.2 h following oral administration. 3-MP pretreatment mitigates lipopolysaccharide (LPS)-induced inflammation in cellular human PBMCs and, in rat studies, 3-MP pretreatment lowers proinflammatory cytokine levels in the conditioned media and in plasma and the brain, respectively. Administered systemically to rats challenged with middle cerebral artery occlusion (MCAo) and reperfusion, 3-MP post-MCAo treatment reduced infarction volume; improved body asymmetry, a behavioral measure of stroke impact; and lowered inflammation. In summary, 3-MP exerted neuroprotective effects via anti-inflammatory actions against MCAo-induced ischemic injury and represents a therapeutic that warrants further investigation as a treatment for brain damage and related disorders associated with excessive inflammation.

GLP-1 receptor (GLP-1R) agonists, widely used for diabetes and obesity management, have shown preclinical and clinical promise as potential therapeutics for neurological conditions. Until 2026, all U.S. Food and Drug Administration (FDA)-approved GLP-1 drugs were peptide-based, with most requiring daily or weekly subcutaneous injections. Despite their large size and low brain penetrance, several peptide-based GLP-1 drugs are in clinical trials for neurologic indications. Recently, the FDA approved orforglipron as the first small-molecule, non-peptide, orally bioavailable human GLP-1 receptor agonist, and it may offer advantages over peptide-based counterparts. We hence evaluated whether it possesses similar neurotrophic, neuroprotective, and anti-inflammatory attributes. Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties. Orforglipron activated cAMP signaling and shielded neuronal cells from excitotoxic glutamate and oxidative stress, which are common in neurodegenerative diseases and injuries. Additionally, orforglipron effectively mitigated LPS- and glutamate-induced proinflammatory protein secretion (IL-6, IL-8, and MCP-1) from a human microglial cell line. Actions were replicated under insulin resistance—a potential cause of neurodegenerative conditions—in which orforglipron significantly upregulated phosphorylation of protein kinase B (Akt), providing an additional neuroprotective mechanism. Measured orforglipron brain uptake in rat was low (brain/plasma and CSF/plasma ratios: 0.0078), and in the ballpark of peptide-based GLP-1 drugs. Nevertheless, orforglipron may provide potential value in specific neurological conditions.