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Summary Dietary iron intake and systemic iron balance are implicated in colorectal cancer (CRC) development, but the means by which iron contributes to CRC are unclear. Gene expression and functional studies demonstrated that the cellular iron importer, divalent metal transporter 1 (DMT1), is highly expressed in CRC through hypoxia inducible factor 2α-dependent transcription. Colon-specific Dmt1 disruption resulted in a tumor-selective inhibitory effect of proliferation in mouse colon tumor models. Proteomic and genomic analysis identified an iron-regulated signaling axis mediated by cyclin dependent kinase 1 (CDK1), JAK1 and STAT3 in CRC progression. A pharmacological inhibitor of DMT1 antagonized the ability of iron to promote tumor growth in a CRC mouse model and a patient-derived CRC enteroid orthotopic model. Our studies implicate a growth-promoting signaling network instigated by elevated intracellular iron levels in tumorigenesis, offering molecular insights into how a key dietary component may contribute to CRC.

The expression of long non-coding RNAs (lncRNAs) is dysregulated in hepatocellular carcinoma (HCC). However, the functions and contributions of lncRNAs remain largely unknown. Here, we identified a critical role of SNHG6-003 in HCC. We found that five SNHG6 transcripts were differentially expressed in HCC tissues while only the SNHG6-003 had an oncogenic function. Ectopic expression of SNHG6-003 in HCC cells promoted cell proliferation and induced drug resistance, whereas SNHG6-003 knockdown promoted apoptosis. Moreover, SNHG6-003 functioned as a competitive endogenous RNA (ceRNA), effectively becoming sponge for miR-26a/b and thereby modulating the expression of transforming growth factor-β-activated kinase 1 (TAK1). Importantly, expression analysis revealed that both SNHG6-003 and TAK1 were upregulated in human cancers, exhibiting a co-expression pattern. In HCC patients, high expression of SNHG6-003 closely correlated with tumor progression and shorter survival. Thus, targeting the ceRNA network involving SNHG6-003 may be used as a treatment strategy against HCC.

Iron is required for efficient oxygen transport, and hypoxia signaling links erythropoiesis with iron homeostasis. Hypoxia induces a highly conserved signaling pathway in cells under conditions of low O2. One component of this pathway, hypoxia-inducible factor (HIF), is a transcription factor that is highly active in hypoxic cells. The first HIF target gene characterized was EPO, which encodes erythropoietin—a glycoprotein hormone that controls erythropoiesis. The past decade has led to fundamental advances in our understanding of how hypoxia regulates iron levels to support erythropoiesis and maintain systemic iron homeostasis. We review the cell-type specific effects of hypoxia and HIFs in adaptive response to changes in oxygen and iron availability, as well as potential uses of HIF modulators for patients with iron-related disorders.

The remarkable regeneration capability of skeletal muscle depends on the coordinated proliferation and differentiation of satellite cells (SCs). The self-renewal of SCs is critical for long-term maintenance of muscle regeneration potential. Hypoxia profoundly affects the proliferation, differentiation, and self-renewal of cultured myoblasts. However, the physiological relevance of hypoxia and hypoxia signaling in SCs in vivo remains largely unknown. Here, we demonstrate that SCs are in an intrinsic hypoxic state in vivo and express hypoxia-inducible factor 2A (HIF2A). HIF2A promotes the stemness and long-term homeostatic maintenance of SCs by maintaining their quiescence, increasing their self-renewal, and blocking their myogenic differentiation. HIF2A stabilization in SCs cultured under normoxia augments their engraftment potential in regenerative muscle. Conversely, HIF2A ablation leads to the depletion of SCs and their consequent regenerative failure in the long-term. In contrast, transient pharmacological inhibition of HIF2A accelerates muscle regeneration by increasing SC proliferation and differentiation. Mechanistically, HIF2A induces the quiescence and self-renewal of SCs by binding the promoter of the Spry1 gene and activating Spry1 expression. These findings suggest that HIF2A is a pivotal mediator of hypoxia signaling in SCs and may be therapeutically targeted to improve muscle regeneration.

Several distinct congenital disorders can lead to tissue-iron overload with anemia. Repeated blood transfusions are one of the major causes of iron overload in several of these disorders, including β-thalassemia major, which is characterized by a defective β-globin gene. In this state, hyperabsorption of iron is also observed and can significantly contribute to iron overload. In β-thalassemia intermedia, which does not require blood transfusion for survival, hyperabsorption of iron is the leading cause of iron overload. The mechanism of increased iron absorption in β-thalassemia is unclear. We definitively demonstrate, using genetic mouse models, that intestinal hypoxia-inducible factor-2α (HIF2α) and divalent metal transporter-1 (DMT1) are activated early in the pathogenesis of β-thalassemia and are essential for excess iron accumulation in mouse models of β-thalassemia. Moreover, thalassemic mice with established iron overload had significant improvement in tissue-iron levels and anemia following disruption of intestinal HIF2α. In addition to repeated blood transfusions and increased iron absorption, chronic hemolysis is the major cause of tissue-iron accumulation in anemic iron-overload disorders caused by hemolytic anemia. Mechanistic studies in a hemolytic anemia mouse model demonstrated that loss of intestinal HIF2α/DMT1 signaling led to decreased tissue-iron accumulation in the liver without worsening the anemia. These data demonstrate that dysregulation of intestinal hypoxia and HIF2α signaling is critical for progressive iron overload in β-thalassemia and may be a novel therapeutic target in several anemic iron-overload disorders.

Brown adipose tissue (BAT) undergoes rapid postnatal development and then protects against cold and obesity into adulthood. However, the molecular mechanism that determines postnatal development and maturation of BAT is largely unknown. Here we show that METTL3 (a key RNA methyltransferase) expression increases significantly in interscapular brown adipose tissue (iBAT) after birth and plays an essential role in the postnatal development and maturation of iBAT. BAT-specific deletion of Mettl3 severely impairs maturation of BAT in vivo by decreasing m 6 A modification and expression of Prdm16, Pparg, and Ucp1 transcripts, which leads to a marked reduction in BAT-mediated adaptive thermogenesis and promotes high-fat diet (HFD)-induced obesity and systemic insulin resistance. These data demonstrate that METTL3 is an essential regulator that controls iBAT postnatal development and energy homeostasis.

Clarifying mechanisms underlying the ecological succession of gut microbiota is a central theme of gut ecology. Under experimental manipulations of zebrafish hatching and rearing environments, we test our core hypothesis that the host development will overwhelm environmental dispersal in governing fish gut microbial community succession due to host genetics, immunology, and gut nutrient niches. We find that zebrafish developmental stage substantially explains the gut microbial community succession, whereas the environmental effects do not significantly affect the gut microbiota succession from larvae to adult fish. The gut microbiotas of zebrafish are clearly separated according to fish developmental stages, and the degree of homogeneous selection governing gut microbiota succession is increasing with host development. This study advances our mechanistic understanding of the gut microbiota assembly and succession by integrating the host and environmental effects, which also provides new insights into the gut ecology of other aquatic animals.