Medicinal chemistry review of the NEET protein family (mitoNEET/CISD1, CISD2, CISD3) and small‑molecule ligands that modulate their redox‑active [2Fe‑2S] clusters and roles in mitochondrial bioenergetics, mitophagy, and iron metabolism.

Because mitochondrial dysfunction, defective mitophagy, and iron dysregulation are central to Parkinson's pathogenesis, the review's focus on druggable NEET proteins and existing ligand chemistry (including pioglitazone off‑target engagement) provides a tangible translational path and repurposing…

Members of the NEET family of proteins are of interest as drug targets in several age-related diseases, including cancer, diabetes, obesity, Alzheimer's and Parkinson's disease, stroke, and traumatic brain injury. These proteins share a CDGSH motif and redox-active [2Fe-2S] clusters. MitoNEET (CDGSH iron-sulfur domain-containing protein 1) is an outer mitochondrial membrane protein that was recently discovered as an off-target of the antidiabetic drug pioglitazone, and plays an essential role in mitochondrial bioenergetics, mitophagy, and iron metabolism. CDGSH iron-sulfur domain-containing protein 2 (nutrient-deprivation autophagy factor 1) is located on the endoplasmic reticulum and is found to be antiaging and associated with Wolfram Syndrome 2, while CDGSH iron-sulfur domain-containing protein 3 (mitochondrial inner NEET protein) is present in the mitochondrial matrix. In this review, we will evaluate the state of the field in the development of NEET protein interacting ligands, which can serve as pharmacological tools to study the biology/biochemistry of NEET family proteins in disease. The NEET family represents a novel class of drug targets, enabling the development of novel treatment modalities to modulate disease progression in various human disorders.