Iron, an indispensable element for life, is involved in all kinds of important physiological activities. Iron promotes cell growth and proliferation, but it also causes oxidative stress damage. The body has a strict regulation mechanism of iron metabolism due to its potential toxicity. As a cancer of the bone marrow and blood cells, leukemia threatens human health seriously. Current studies suggest that dysregulation of iron metabolism and subsequent accumulation of excess iron are closely associated with the occurrence and progress of leukemia. Specifically, excess iron promotes the development of leukemia due to the pro-oxidative nature of iron and its damaging effects on DNA. On the other hand, leukemia cells acquire large amounts of iron to maintain rapid growth and proliferation. Therefore, targeting iron metabolism may provide new insights for approaches to the treatment of leukemia. This review summarizes physiologic iron metabolism, alternations of iron metabolism in leukemia and therapeutic opportunities of targeting the altered iron metabolism in leukemia, with a focus on acute leukemia.

Multiple myeloma (MM) cells derive proliferative signals from the bone marrow (BM) microenvironment via exosomal crosstalk. Therapeutic strategies targeting this crosstalk are still lacking. Bortezomib resistance in MM cells is linked to elevated expression of xCT (the subunit of system Xc^-). Extracellular glutamate released by system Xc^- can bind to glutamate metabotropic receptor (GRM) 3, thereby upregulating Rab27-dependent vesicular trafficking. Since Rab27 is also involved in exosome biogenesis, we aimed to investigate the role of system Xc^- in exosomal communication between BM stromal cells (BMSCs) and MM cells. We observed that expression of xCT and GRMs was increased after bortezomib treatment in both BMSCs and MM cells. Secretion of glutamate and exosomes was simultaneously enhanced which could be countered by inhibition of system Xc^- or GRMs. Moreover, glutamate supplementation increased exosome secretion by increasing expression of Alix, TSG101, Rab27a/b and VAMP7. Importantly, the system Xc^- inhibitor sulfasalazine reduced BMSC-induced resistance to bortezomib in MM cells in vitro and enhanced its anti-MM effects in vivo. These findings suggest that system Xc^- plays an important role within the BM and could be a potential target in MM.

Background: Mitochondria are the primary organelles that regulate cellular bioenergetic metabolism and maintain homeostasis, providing essential structural support for optimal cell survival. Nonetheless, advancing age leads to cumulative damage to mitochondrial structure and functional integrity, which is a defining characteristic of biological aging and is closely linked to the emergence and progression of numerous age-related diseases, including neurodegenerative disorders, cardiovascular diseases, and metabolic disorders. Scope of review: This article offers a thorough summary and review of mitochondrial quality control (MQC), emphasizing numerous critical processes, including mitochondrial biosynthesis, dynamic remodeling (fusion and fission), and mitophagy. We thoroughly elucidate the molecular pathways that regulate MQC and demonstrate how age-related dysregulation precipitates cellular senescence, highlighting the transition from physiological maintenance to pathological malfunction, which ultimately culminates in cellular aging. Conclusions and implications: This study systematically elaborates the pathophysiological mechanisms in the field, comprehensively evaluates the clinical translational potential of targeting the MQC pathway, highlights the key objectives of “restoring mitochondrial plasticity and removing dysfunctional mitochondria”, and explores novel intervention strategies. The restoration of normal mitochondrial function in cells throughout aging is a very promising path for precision medicine therapeutics with great translational potential, according to recent state-of-the-art research. The development of novel therapeutic approaches to improve functional healthy mitochondria can effectively delay aging and reduce the rising global burden of age-related diseases.