Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects.

The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis.

Treating incurable non-communicable diseases by targeting iron metabolism and ferroptosis.

Both iron metabolism and ferroptosis (an iron-dependent form of programmed cell death) have been connected to the development and progression of many currently incurable non-communicable diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, metabolic dysfunction-associated steatohepatitis, heart failure, and both treatment-relapsed and refractory cancers, such as pancreatic ductal adenocarcinoma and triple-negative breast cancer. Thus, understanding the relationship between iron and these diseases can pave the way for the development of novel therapeutic strategies. Here, we summarize the latest evidence supporting the pathological roles of dysregulated iron metabolism and ferroptosis in a wide range of preclinical animal models of these currently incurable non-communicable diseases.

SLC39A10 is a key zinc transporter in T cells and its loss mitigates autoimmune disease.

Zinc homeostasis plays an essential role in maintaining immune function and is tightly regulated by zinc transporters. We previously reported that the zinc transporter SLC39A10, located in the cell membrane, critically regulates the susceptibility of macrophages to inflammatory stimuli; however, the functional role of SLC39A10 in T cells is currently unknown. Here, we identified two SNPs in SLC39A10 that are associated with inflammatory bowel disease (IBD).

Adipocyte-derived ferroptotic signaling mitigates obesity.

Ferroptosis is characterized as an iron-dependent and lipophilic form of cell death. However, it remains unclear what role ferroptosis has in adipose tissue function and activity. Here, we find a lower ferroptotic signature in the adipose tissue of individuals and mice with obesity.

The zinc transporter Slc30a1 (ZnT1) in macrophages plays a protective role against attenuated .

The zinc transporter Slc30a1 plays an essential role in maintaining cellular zinc homeostasis. Despite this, its functional role in macrophages remains largely unknown. Here, we examine the function of Slc30a1 in host defense using mice models infected with an attenuated stain of Typhimurium and primary macrophages infected with the attenuated .

The Intestinal Transporter SLC30A1 Plays a Critical Role in Regulating Systemic Zinc Homeostasis.

The essential trace element, zinc, regulates virtually all aspects of cellular physiology, particularly cell proliferation and survival. Diverse families of metal transporters, metallothioneins, and metal-responsive transcriptional regulators are linked to zinc homeostasis. However, the mechanism underlying the regulation of systemic zinc homeostasis remains largely unknown.

Iron homeostasis and ferroptosis in human diseases: mechanisms and therapeutic prospects.

Iron, an essential mineral in the body, is involved in numerous physiological processes, making the maintenance of iron homeostasis crucial for overall health. Both iron overload and deficiency can cause various disorders and human diseases. Ferroptosis, a form of cell death dependent on iron, is characterized by the extensive peroxidation of lipids.

Essentiality of SLC7A11-mediated nonessential amino acids in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) remains a rapidly growing global health burden. Here, we report that the nonessential amino acid (NEAA) transporter SLC7A11 plays a key role in MASLD. In patients with MASLD, we found high expression levels of SLC7A11 that were correlated directly with clinical grade.

Integrative clinical and preclinical studies identify FerroTerminator1 as a potent therapeutic drug for MASH.

The complex etiological factors associated with metabolic dysfunction-associated fatty liver disease (MAFLD), including perturbed iron homeostasis, and the unclear nature by which they contribute to disease progression have resulted in a limited number of effective therapeutic interventions. Here, we report that patients with metabolic dysfunction-associated steatohepatitis (MASH), a pathological subtype of MAFLD, exhibit excess hepatic iron and that it has a strong positive correlation with disease progression. FerroTerminator1 (FOT1) effectively reverses liver injury across multiple MASH models without notable toxic side effects compared with clinically approved iron chelators.

Mendelian Randomization Analysis of Systemic Iron Status and Risk of Different Types of Kidney Disease.

With rapid increases in incidence, diverse subtypes, and complicated etiologies, kidney disease remains a global public health problem. Iron, as an essential trace element, has pleiotropic effects on renal function and the progression of kidney diseases. A two-sample Mendelian randomization (MR) analysis was implemented to determine the potential causal effects between systemic iron status on different kidney diseases.

Programmable melanoma-targeted radio-immunotherapy via fusogenic liposomes functionalized with multivariate-gated aptamer assemblies.

Radio-immunotherapy exploits the immunostimulatory features of ionizing radiation (IR) to enhance antitumor effects and offers emerging opportunities for treating invasive tumor indications such as melanoma. However, insufficient dose deposition and immunosuppressive microenvironment (TME) of solid tumors limit its efficacy. Here we report a programmable sequential therapeutic strategy based on multifunctional fusogenic liposomes (Lip@AUR-ACP-aptPD-L1) to overcome the intrinsic radio-immunotherapeutic resistance of solid tumors.

Activation of Intestinal HIF2α Ameliorates Iron-Refractory Anemia.

In clinics, hepcidin levels are elevated in various anemia-related conditions, particularly in iron-refractory anemia and in high inflammatory states that suppress iron absorption, which remains an urgent unmet medical need. To identify effective treatment options for various types of iron-refractory anemia, the potential effect of hypoxia and pharmacologically-mimetic drug FG-4592 (Roxadustat) are evaluated, a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor, on mouse models of iron-refractory iron-deficiency anemia (IRIDA), anemia of inflammation and 5-fluorouracil-induced chemotherapy-related anemia. The potent protective effects of both hypoxia and FG-4592 on IRIDA as well as other 2 tested mouse cohorts are found.

Hepatic HDAC3 Regulates Systemic Iron Homeostasis and Ferroptosis via the Hippo Signaling Pathway.

Histone deacetylases (HDACs) are epigenetic regulators that play an important role in determining cell fate and maintaining cellular homeostasis. However, whether and how HDACs regulate iron metabolism and ferroptosis (an iron-dependent form of cell death) remain unclear. Here, the putative role of hepatic HDACs in regulating iron metabolism and ferroptosis was investigated using genetic mouse models.

Discovery of 4-hydroxyl pyrazole derivatives as potent ferroptosis inhibitors.

Ferroptosis, an iron-dependent form of regulated cell death, has been well recognized as a pathogenic mechanism in driving many diseases, such as neurodegenerative disorders, ischemia-reperfusion (I/R) injury. Blocking ferroptosis has been emerging as a feasible therapeutic strategy for the prevention and treatment of these diseases. However, novel potent ferroptosis inhibitors remain to be developed for further clinical applications.

Metformin potentiates nephrotoxicity by promoting NETosis in response to renal ferroptosis.

Given the rapidly aging population, aging-related diseases are becoming an excessive burden on the global healthcare system. Metformin has been shown to be beneficial to many age-related disorders, as well as increase lifespan in preclinical animal models. During the aging process, kidney function progressively declines.

Targeting ferroptosis opens new avenues for the development of novel therapeutics.

Ferroptosis is an iron-dependent form of regulated cell death with distinct characteristics, including altered iron homeostasis, reduced defense against oxidative stress, and abnormal lipid peroxidation. Recent studies have provided compelling evidence supporting the notion that ferroptosis plays a key pathogenic role in many diseases such as various cancer types, neurodegenerative disease, diseases involving tissue and/or organ injury, and inflammatory and infectious diseases. Although the precise regulatory networks that underlie ferroptosis are largely unknown, particularly with respect to the initiation and progression of various diseases, ferroptosis is recognized as a bona fide target for the further development of treatment and prevention strategies.

Mechanisms and regulation of defensins in host defense.

As a family of cationic host defense peptides, defensins are mainly synthesized by Paneth cells, neutrophils, and epithelial cells, contributing to host defense. Their biological functions in innate immunity, as well as their structure and activity relationships, along with their mechanisms of action and therapeutic potential, have been of great interest in recent years. To highlight the key research into the role of defensins in human and animal health, we first describe their research history, structural features, evolution, and antimicrobial mechanisms.