GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE329nnn/GSE329028/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE329028GEOGSEfalseChemical N-degrons activate p62-mediated mitophagy to alleviate mitochondrial neuropathiesPharmacological activation of mitophagy offers a promising strategy to eliminate dysfunctional mitochondria. We previously identified the autophagy receptor p62/SQSTM1 as an N-recognin whose activity is enhanced by Arg/N-degrons. Here, we show that Arg/N-degrons generated by ATE1-encoded R-transferase regulate p62-mediated mitophagy by promoting its recruitment to damaged mitochondria. Structural modification of Arg/N-degrons yielded ATB1071, a 443.5-Da orally bioavailable compound that activates p62 and induces stress-selective mitophagy through both Parkin-independent pathways involving NIPSNAP1 and NIPSNAP2, and a Parkin-dependent pathway involving the substrate EBP1/PA2G4. In Ndufs4-/- mice, a Leigh syndrome (LS) model, ATB1071 induced mitophagy in the brain and exerted therapeutic benefits by reducing neuroinflammation, improving muscle strength and neuromuscular coordination, and extending lifespan. In cerebral ischemia-reperfusion (IR) model mice, ATB1071 reduced infarct volume and neuronal death, and ameliorated multiple behavioral deficits through EBP1-dependent mitophagy. Pharmacokinetic (PK) and toxicological analyses support ATB1071 as a preclinical candidate for mitochondria-associated neurological injury.2026/05/09GSE329028GSM9696009GSM9696018GSM9696007GSM9696008GSM9696016GSM9696017GSM9696014GSM9696015GSM9696012GSM9696013GSM9696010GSM969601134328329028Mus musculus