AKR1C2 (Aldo-Keto Reductase Family 1 Member C2)

In 19Del/T790M/C797S mutant cells, SG-55 elevated the reduced/oxidized nicotinamide adenine dinucleotide phosphate (NADPH/NADP+) ratio, decreased the reduced/oxidized glutathione (GSH/GSSG) ratio, induced DNA double-strand breaks, and synergized with Osimertinib to suppress proliferation, clonogenicity, and survival. This combination therapy demonstrated efficacy in xenograft models and exhibited favorable pharmacokinetics in mice, thereby validating AKR1C3 blockade as a "metabolism-targeted" strategy to overcome resistance mediated by the EGFR C797S mutation.

These findings highlighted the potential of AKR1C2 as a predictive biomarker for patient response to CDDP therapy. Additionally, our study established a novel link between histone lactylation and CDDP resistance, providing new insights into the epigenetic regulation in NSCLC.

Molecular docking of the selenium adducts against human AKR1C2 (PDB: 4XO6) indicated modest binding (ΔG ≈ -5.3 kcal·mol-1) compared with 5-fluorouracil (-6.8 kcal·mol-1). Biological screening against MCF-7 cancer cells found higher antiproliferative activity for Ag complexes (IC50 ≈ 13.7 μg·mL-1) than for selenium adducts or salts. The Ag-NHCs also exhibited potent antibacterial activity (MICs ≈ 5-6 μM against E. coli and S. aureus), whereas selenium adduct C2 showed the strongest antioxidant (DPPH) activity (IC50 ≈ 4.9-5.5 μg·mL-1).

This review consolidates current findings on the molecular characteristics, brain region-specific expression, and neurophysiological functions of AKR1C enzymes, and discusses their emerging roles in central nervous system disorders. By presenting these insights, this review offers a valuable framework for researchers to explore new directions in the development of neuroprotective and neuroregenerative strategies.

High-risk patients exhibited poorer outcomes, reduced immune infiltration, and altered drug sensitivity. The MRG prognostic model stratifies PRAD patients by survival and immune landscape, aiding precision immunotherapy and drug discovery.

We screened 6 nitro-containing drugs (flunitrazepam, clonazepam, nimesulide, nilutamide, flutamide, and chloramphenicol) as substrates against recombinant human AKR1C1, AKR1C2, AKR1C3, and AKR1C4, using discontinuous enzymatic assays. We conclude that both AKR1C3 and AKR1C2 may have an important role in flunitrazepam drug response. SIGNIFICANCE STATEMENT: Aldo-keto reductase (AKR)1C3 reduces flunitrazepam to 7-amino-flunitrazepam through the formation of reactive nitroso and hydroxylamino intermediates, and by inhibiting AKR1C2, flunitrazepam may reduce the formation of the neuroactive steroid allopregnanolone.

Finally, using the Genomics of Drug Sensitivity in Cancer and Cancer Therapeutics Response Portal databases, potential drugs [(5Z)-7-oxozeaenol, selumetinib, RDEA119, AZ628, dabrafenib and trametinib] were identified based on the aforementioned seven key carcinogenic genes, focusing on those that targeted multiple genes. In conclusion, the present study identified 14 key ferroptosis-related genes, and seven key carcinogenic genes, which represent promising novel molecular targets for the prognosis and treatment of GC.

The natural flavanone hesperidin and its aglycone hesperetin were identified as human aldo-keto reductase family 1 member C1 (AKR1C1) and AKR1C2 inhibitors via chemoproteomic profiling, which provides mechanistic insight into their chemosensitization effects in cancer therapy.

These findings suggest that corilagin regulates glutathione metabolism by targeting AKR1C2, thereby inhibiting caspase-1/gasdermin D-dependent pyroptosis and ameliorating radiation enteritis. Based on these results, corilagin is a promising protective agent for radiation enteritis, with immense potential for future research and clinical applications.

Our study demonstrates that AKR1C2 knockdown promotes ferroptosis and inhibits malignant biological behaviors in lung cancer cells.

These findings indicate that the abnormal expression of claudin-1 promotes tumor progression and drug resistance through its interaction with aldo-keto reductase proteins, highlighting claudin-1 and aldo-keto reductase family proteins as potential biomarkers and therapeutic targets for pancreatic cancer.

The acquired resistance of doxorubicin (DOX) significantly limits their application in breast cancer treatment...Utilizing highly DOX resistant MCF-7/ADR cells, 29 demonstrated superior potential as a therapeutic agent for re-sensitizing drug-resistant cell lines to chemotherapy both in vitro and in vivo, suggesting that pan-inhibition of AKR1C1-1C4 may serve as a more promising therapeutic strategy for drug-resistant breast cancer. In summary, Compound 29 may be a promising therapeutic adjuvant in the development of novel strategies to overcome drug resistance.