AKR1C1 is a cytosolic oxidoreductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids, displaying broad substrate specificity 1. It primarily generates 20α-hydroxysteroids and plays critical roles in steroid hormone metabolism, particularly progesterone inactivation and neurosteroid production 2. AKR1C1 reduces progesterone to less potent metabolites, potentially regulating progesterone receptor ligand availability, and converts the neuroactive steroid 3α,5α-THP to less potent forms, modulating GABAAR-mediated neural signaling. In inflammation-induced parturition, IL-1β upregulates AKR1C1 expression in decidual stromal cells, promoting progesterone inactivation and labor initiation; AKR1C1 inhibition prevents preterm birth in mouse models 3. AKR1C1 demonstrates significant disease relevance in cancer biology. It protects corneal epithelial cells from oxidative stress-induced ferroptosis in dry eye disease through NRF2-mediated upregulation 4. In extrahepatic cholangiocarcinoma, elevated AKR1C1 promotes tumorigenicity by suppressing CYP1B1-mediated ferroptosis via ubiquitin-proteasomal degradation and AHR-mediated transcriptional repression; AKR1C1 depletion sensitizes tumors to ferroptosis inducers 5. Similarly, in triple-negative breast cancer, AKR1C1 enhances GPX4 ubiquitination and degradation to suppress ferroptosis 6. AKR1C1 is upregulated in STK11/KEAP1 co-mutant lung adenocarcinoma, conferring ferroptosis resistance 7. These findings position AKR1C1 inhibition as a promising therapeutic strategy for hormone-dependent cancers and ferroptosis-resistant malignancies.