Exploiting selective aldo-keto reductase 1C3 inhibitors and beyond: recent advances and future directions in cancer therapy.

Conventional cancer therapy has long been confronted by significant challenges, particularly drug resistance. Aldo-keto reductase family 1 member C3 (AKR1C3), an enzyme markedly overexpressed in diverse human malignancies and critically implicated in tumor progression and therapy resistance, has emerged as an attractive target for pharmacological intervention. To date, considerable progress has been made in the development of selective AKR1C3 inhibitors, giving rise to diverse classes of compounds ranging from classical cinnamic acid derivatives, steroids, benzamide and benzopyran derivatives to non-steroidal anti-inflammatory drug (NSAID) analogs, alongside emerging extensions such as multi-target AKR1C3 inhibitors and AKR1C3-dependent prodrugs. In particular, combining these agents with established chemotherapeutic agents such as enzalutamide has demonstrated robust antitumor efficacy and the capacity to overcome drug resistance in animal models. However, their clinical translation remains limited. In this review, we discuss the structural characteristics of AKR1C3 and its distinctions from other isoforms, elucidate its multifaceted roles across various cancers, and summarize the current landscape of AKR1C3 inhibitors. We further highlight key challenges and outline perspectives to advance AKR1C3-targeted strategies in cancer treatment.