Current Drug Targets - Volume 26, Issue 11, 2025

Creatine kinases (CKs) are a family of vital enzymes implicated in the domain of cellular bioenergy, fulfilling a pivotal role in facilitating the reversible transfer of phosphoryl groups between adenosine triphosphate (ATP) and creatine. This process plays a crucial role in maintaining optimal ATP levels during energy-demanding processes, a requirement that is amplified in rapidly proliferating cells, including cancerous cells. CKs are pivotal in supporting cancer growth and metastasis, making their inhibition a promising therapeutic strategy. The present review discusses a few ways of disrupting the creatine energy production cycle with emphasis on three main areas of research: First, we consider the different strategies that attack the Creatine Transporter (SLC6A8). Since this transporter facilitates the entry of creatine into the cell, it is expected that inhibiting this transporter may lead to reduced availability of creatine for CK-mediated energy production. Second, strategies aimed at directly inhibiting the enzyme carrying out the creatine phosphorylation are described. Lastly, we consider approaches targeting the backward reaction, i.e., the re-conversion of phosphocreatine to creatine and, thereby, the equilibrium of the CK reaction. The current review gives an overview of the structure-activity and structure-property relationships of the currently available CK inhibitors. Understanding these relations in depth is a prerequisite for developing new and more potent and selective CK inhibitors. This review focuses on an in-depth analysis to create better CK inhibitors with possible applications in oncology.

In the past several years, human life expectancy has increased dramatically, and the global aging process is accelerating at an unprecedented rate. Impaired organ functions and systemic inflammation increase the risk of aging-related diseases. It seriously affects the quality of life in older adults and places a heavy burden on the global economy and public health. Inflammation is the cornerstone of many age-related diseases, and among various inflammatory mediators, Prostaglandin E2 (PGE2) has emerged as a key player. For example, PGE2 could participate in the progression of Alzheimer's disease (AD) by modulating neuroinflammation. Plasma PGE2 is regarded as a potential and specific diagnostic biomarker, and higher initial PGE2 levels are positively correlated with longer survival in AD. PGE2 also mediates bone and muscle metabolism to affect age-related musculoskeletal diseases, including sarcopenia, osteoporosis, and osteoarthritis. It activates the EP4 receptor on sensory nerves to inhibit sympathetic nerve activity and modulate bone formation. Moreover, the PGE2/EP4 axis positively regulates muscle mass and strength. In diabetes, increased Cox-2 and m-PGES2 promote PGE2 production. The activated PGE2/EP3 axis exacerbates the progression of type 2 diabetes (T2D) by impairing glucose metabolism and accelerating β-cell senescence. Therefore, the role of PGE2 in age-related diseases deserves greater attention. Its involvement is driven by the dysregulation of its biosynthesis, metabolism, and receptor-mediated signaling. Regulating the concentration of PGE2 or modulating receptor activity represents a promising therapeutic strategy for managing age-related diseases.

Lipidomics, a cutting-edge branch of metabolomics provides a comprehensive understanding of the lipidome and its alterations in cellular and systemic processes. In Breast Cancer (BC), a highly heterogeneous disease, lipidomics has emerged as a pivotal tool for exploring metabolic reprogramming, tumor progression, and therapeutic resistance. This review highlights the intricate relationship between lipid metabolism and breast cancer, with a focus on subtype-specific lipid dependencies, oxidative stress, and ferroptosis. Technological advancements, such as mass spectrometry and chromatography, have enabled precise profiling of lipid alterations, revealing distinct lipid signatures across breast cancer subtypes. Key enzymes like acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), along with lipid regulators like PPARγ, have been identified as central players in lipid-driven tumorigenesis. Lipidomic studies offer the potential for biomarker discovery and the development of lipid-targeted therapies. Despite challenges in standardization and integration with other omics approaches, lipidomics is poised to revolutionize breast cancer diagnostics and therapeutics, providing novel insights into the metabolic underpinnings of this complex disease.