Targeting the Na+/K+ ATPase DR-region with DR-Ab improves doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is a potent chemotherapeutic drug for various cancers. Yet, the cardiotoxic side effects limit its application in clinical uses, in which ferroptosis serves as a crucial pathological mechanism in DOX-induced cardiotoxicity (DIC). A reduction of Na+/K + ATPase (NKA) activity is closely associated with DIC progression. However, whether abnormal NKA function was involved in DOX-induced cardiotoxicity and ferroptosis remains unknown. Here, we aim to decipher the cellular and molecular mechanisms of dysfunctional NKA in DOX-induced ferroptosis and investigate NKA as a potential therapeutic target for DIC. A decrease activity of NKA further aggravated DOX-triggered cardiac dysfunction and ferroptosis in NKAα1 haploinsufficiency mice. In contrast, antibodies against the DR-region of NKAα-subunit (DR-Ab) attenuated the cardiac dysfunction and ferroptosis induced by DOX. Mechanistically, NKAα1 interacted with SLC7A11 to form a novel protein complex, which was directly implicated in the disease progression of DIC. Furthermore, the therapeutic effect of DR-Ab on DIC was mediated by reducing ferroptosis by promoting the association of NKAα1/SLC7A11 complex and maintaining the stability of SLC7A11 on the cell surface. These results indicate that antibodies targeting the DR-region of NKA may serve as a novel therapeutic strategy to alleviate DOX-induced cardiotoxicity.

Recent Advances in the Study of Na+/K+-ATPase in Neurodegenerative Diseases.

Na+/K+-ATPase (NKA), a large transmembrane protein, is expressed in the plasma membrane of most eukaryotic cells. It maintains resting membrane potential, cell volume and secondary transcellular transport of other ions and neurotransmitters. NKA consumes about half of the ATP molecules in the brain, which makes NKA highly sensitive to energy deficiency. Neurodegenerative diseases (NDDs) are a group of diseases characterized by chronic, progressive and irreversible neuronal loss in specific brain areas. The pathogenesis of NDDs is sophisticated, involving protein misfolding and aggregation, mitochondrial dysfunction and oxidative stress. The protective effect of NKA against NDDs has been emerging gradually in the past few decades. Hence, understanding the role of NKA in NDDs is critical for elucidating the underlying pathophysiology of NDDs and identifying new therapeutic targets. The present review focuses on the recent progress involving different aspects of NKA in cellular homeostasis to present in-depth understanding of this unique protein. Moreover, the essential roles of NKA in NDDs are discussed to provide a platform and bright future for the improvement of clinical research in NDDs.

Nitroxyl as a Potential Theranostic in the Cancer Arena.

Significance: As one-electron reduced molecule of nitric oxide (NO), nitroxyl (HNO) has gained enormous attention because of its novel physiological or pharmacological properties, ranging from cardiovascular protective actions to antitumoricidal effects. Recent Advances: HNO is emerging as a new entity with therapeutic advantages over its redox sibling, NO. The interests in the chemical, pharmacological, and biological characteristics of HNO have broadened our current understanding of its role in physiology and pathophysiology. Critical Issues: In particular, the experimental evidence suggests the therapeutic potential of HNO in tumor pharmacology, such as neuroblastoma, gastrointestinal tumor, ovarian, lung, and breast cancers. Indeed, HNO donors have been demonstrated to attenuate tumor proliferation and angiogenesis. Future Directions: In this review, the generation and detection of HNO are outlined, and the roles of HNO in cancer progression are further discussed. We anticipate that the completion of this review might give novel insights into the roles of HNO in cancer pharmacology and open up a novel field of cancer therapy based on HNO.