AKR1C3 (Aldo-Keto Reductase Family 1 Member C3)

For experimental validation, umbelliprenin (UMB) was extracted from Ferula persica by preparative thin layer chromatography, and then, KYSE-30 cells were treated with UMB, alone and in combination with paclitaxel (PTX) for 48 h...The present findings highlight the potential of natural coumarins, particularly UMB, to inhibit the reductase activity of AKR1C3, thereby enhancing the efficacy of chemotherapy and radiotherapy. This positions UMB as a promising candidate for overcoming chemoradioresistance in GI carcinomas and paves the way for the development of innovative therapeutic strategies.

P2, N=75, Not yet recruiting, Nanjing Tianyi Mountain Hospital; Nanjing Tianyi Mountain Hospital

We also demonstrate that loss of KEAP1 reduces sensitivity of RET fusion-positive cells to selpercatinib, consistent with previous reports that these alterations promote drug resistance in other malignancies. In this study, we comprehensively profile KEAP1 mutations in thyroid tumors, showing that they are more prevalent and functionally significant than previously recognized. These findings position KEAP1 mutations as novel oncogenic variants in thyroid cancer and support the integration of KEAP1/NRF2 pathway profiling into future studies and clinical frameworks.

In addition, AKR1C3 overexpression promoted aerobic glycolysis in HSCs by activating the AKT/mTOR pathway, but these effects were partly reversed by glycolysis inhibitors (2-DG) and AKT inhibitors (MK-2206). Our findings revealed the mechanism by which AKR1C3 promotes LF, suggesting that AKR1C3 may serve as a potential therapeutic target for LF, warranting further studies.

In conclusion, these findings suggest that THs regulate adrenal androgen production by modulating the activity of key steroidogenic enzymes. This relationship appears to be predominantly unidirectional, as THs influence adrenal steroidogenesis but adrenal androgens do not alter HPT axis function.

In silico ADMET profiling largely met Lipinski rules of five, predicted good intestinal absorption, limited CNS exposure, and few hepatotoxicity alerts, though some compounds require further toxicity evaluation. Together, these results position H. apicalis propolis as a phenolic-rich source of multi-target hepatoprotective and chemopreventive candidates, meriting in vivo validation and detailed ADME/toxicity studies.

Single-cell analysis indicated specific expression of AKR1C3 in HCC cells, while molecular docking analysis showed that, among the five potential targets, AKR1C3 demonstrated the most stable binding affinity to rutin. Our findings suggest that rutin may modulate ferroptosis in HCC, with rutin associated ferroptosis genes implicated in disease biology; moreover, the proposed risk scoring model shows promising prognostic utility in HCC.

We highlight its mechanistic involvement in tumor-promoting pathways and systematically summarize recent advances in the discovery and optimization of AKR1C3 inhibitors from 2021 to 2025. Special emphasis is placed on the medicinal chemistry strategies employed, structure-activity relationship (SAR) trends, and translational potential of representative inhibitors.

Furthermore, high DHRS2 predicts better survival specifically in male patients, indicating sex-specific androgen involvement. Overall, these findings elucidate the epigenetic mechanism underlying the cisplatin-sensitizing effect of Entinostat, and identifies the DHRS2-AKR1C3-androgen axis as a potential target, particularly for male patients.

CAS significantly enhanced ABI's cytotoxic efficacy in 22Rv1 cells, as evidenced by synergistic interactions (CI: 0.31-0.71); however, no such synergy was observed in LNCaP cells or with enzalutamide. Docking and molecular dynamics simulations indicated a stable CAS-AKR1C3 interaction, characterized by crucial hydrogen bonding and aromatic stacking within the active site. These results suggest that CAS is a promising chemosensitizer targeting AKR1C3 to overcome ABI resistance in CRPC.

Our in vitro data demonstrate that tirabrutinib influences daunorubicin pharmacodynamics by targeting both metabolic and transport pathways. However, Chou - Talalay analysis highlights the importance of appropriate dosing to achieve therapeutic synergy in combination regimens.

This study provides novel insight into the molecular mechanism of RA and highlights its therapeutic potential as a ferroptosis inducer for colorectal cancer treatment. The online version contains supplementary material available at 10.1007/s13205-025-04551-8.