AKR1C1 (Aldo-Keto Reductase Family 1 Member C1)

AKR1C1 activation drived lipid metabolic dysregulation characterized by enhanced fatty acid synthesis, thereby facilitating metabolic adaptation and survival during early LUSC carcinogenesis. Collectively, our findings identified AKR1C1 as an early-response biomarker and a pivotal metabolic node controlling FASN-dependent lipid metabolic reprogramming in LUSC.

We also demonstrated that chemical inhibition of these proteins using RSL3 (GPX4 inhibitor) and erastin (xCT inhibitor) significantly suppressed osteosarcoma cell growth. Collectively, our findings reveal that GPX4 inhibition initiates ferroptosis while simultaneously activating NRF2-driven antioxidant defenses, iron homeostasis mechanisms, and adaptive cell survival signaling. The results highlight potential therapeutic strategies that combine GPX4 inhibition with targeted disruption of compensatory pathways to overcome ferroptosis resistance in osteosarcoma.

An association between the genes implicated in cancer-related processes and some transcription factors was observed. In conclusion, PM10 has strong modulatory effects on the PBMCs transcriptome, suggesting that genetic remodeling may lead to cancer.

© 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

Given that AKR1C1-3 isoenzymes often catalyze overlapping biochemical transformations, inhibition of one member may be compensated by another. Thus, while selective AKR1C inhibitors remain valuable, the development of pan-inhibitors also represents a promising therapeutic strategy.

Overall, this comprehensive computational analysis highlights previously uncharacterized deleterious coding and regulatory variants of AKR1C1 with potential relevance to disease susceptibility and cancer progression. These findings provide a valuable framework for future experimental validation and risk assessment studies involving AKR1C1.

In 3D spheroids, both agents disrupted tumor architecture and reduced viability, alone or in combination with carboplatin. Our findings highlight that platinum resistance in HGSOC can be tackled by repurposing MEF and MPA that act also as AKR1C inhibitors.

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.

ADMET profiling confirmed SFN's high intestinal absorption and blood-brain barrier non-permeability. Thus, integrating SFN as a natural AKR1B10 inhibitor into ER-negative BC treatment regimens may enhance early malignancy management and support its development as a nutraceutical adjunct.

AKR1Cs are not only significantly overexpressed in pancreatic cancer, but also closely associated with poor clinical grading, clinical chemoresistance and poor immune response in pancreatic cancer.Moreover, regulating the expression of AKR1C1 in pancreatic cancer cells will affect its proliferation, migration, invasion and the occurrence of epithelial-mesenchymal transformation (EMT). Our findings are expected to establish AKR1Cs, especially AKR1C1 as a promising therapeutic target for the clinical treatment of pancreatic cancer.

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.

Our findings suggest that ZnS inhibits autophagy, promotes ferroptosis, and enhances sensitivity to sorafenib in HCC cells through the lncRNA TCONS-00026762/AKR1C1 axis.