NRF2 mutation enhances the immune escape of hepatocellular carcinoma by reducing STING activation.

The nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor usually hyperactivated in hepatocellular carcinoma (HCC). In addition, about 14 % of HCC patients carry mutation in NRF2 or Kelch-like ECH-associated protein 1 (Keap1), a NRF2 inhibitor, both of which lead to constitutive activation of NRF2. It has been widely reported that NRF2 plays important roles in the proliferation, differentiation and metastasis of tumor cells. But as an important gene involved in antioxidation and anti-inflammation, little studies have focused on its role in tumor immune escape. Here we found that NRF2 gain-of-function mutation leads to reduced expression of STING and decreased infiltration of peripheral immune cells through which way it helps the tumor cells to evade from immune surveillance. This phenomenon can be reversed by STING overexpression. Our study also revealed that NRF2 mutation greatly reduced the effect of STING activating based immunotherapy. It is important to simultaneously inhibit the activity of NRF2 when using STING agonist for the treatment of HCC patients carrying NRF2 mutation.

IRON MAN interacts with Cu-DEFICIENCY INDUCED TRANSCRIPTION FACTOR 1 to maintain copper homeostasis.

Copper (Cu) is essential for plant growth and development. IRON MAN (IMA) is a family of small peptides that can bind both iron (Fe) and Cu ions. It was reported that IMAs mediate Fe homeostasis in Arabidopsis thaliana. However, it remains unclear whether IMAs are involved in Cu homeostasis. The transcript abundance of IMA genes decreased in response to Cu deficiency. The combined disruption of all IMA genes caused enhanced tolerance to Cu deficiency and resulted in an increase in the transcript abundance of Cu uptake genes, whereas the overexpression of IMA1 or IMA3 led to the opposite results. Protein interaction assays indicated that IMAs interact with Cu-DEFICIENCY INDUCED TRANSCRIPTION FACTOR1 (CITF1), which is a positive regulator of the Cu uptake genes. Further studies showed that IMAs not only interfere with the DNA binding of CITF1 but also repress the transcriptional activation activity of CITF1, hence resulting in downregulation of the Cu uptake genes. Genetic analyses indicated that IMAs modulate Cu homeostasis in a CITF1-dependent manner. Our findings indicate that IMAs inhibit the functions of CITF1 in regulating Cu deficiency responses, thereby providing a conceptual framework for comprehending the regulation of Cu homeostasis.

Metal-Organic Framework Based Sensors for Benzene Vapor.

Sensing of benzene vapor is a hot spot due to the volatile drastic carcinogen even at trace concentration. However, achieving convenient and rapid detection is still a challenge. As a sort of functional porous material, metal-organic frameworks (MOFs) have been developed as detection sensors by adsorbing benzene vapor and converting it into other signals (fluorescence intensity/wavelength, chemiresistive, weight or color, etc.). Supramolecular interaction between benzene molecules and the host framework, aperture size/shape and structural flexibility are influential factors in the performance of MOF-based sensors. Therefore, enhancing the host-guest interactions between the host framework and benzene molecules, or regulating the diffusion rate of benzene molecules by changing the aperture size/shape and flexibility of the host framework to enhance the detection signal are effective strategies for constructing MOF-based sensors. This concept highlights several types of MOF-based sensors for the detection of benzene vapor.

Refractive associations with corneal biomechanical properties among young adults: a population-based Corvis ST study.

PURPOSE: To assess the associations of corneal biomechanical properties as measured by the Corvis ST with refractive errors and ocular biometry in an unselected sample of young adults. METHODS: A total of 1645 healthy university students underwent corneal biomechanical parameters measurement by the Corvis ST. The refractive status of the participants was measured using an autorefractor without cycloplegia. Ocular biometric parameters were measured using the IOL Master. RESULTS: After adjusting for the effect of age, sex, biomechanical-corrected intraocular pressure and central corneal thickness, axial length was significantly associated with A1 velocity (A1v, ß = -10.47), A2 velocity (A2v, ß = 4.66), A2 deflection amplitude (A2DeflA, ß = -6.02), HC deflection amplitude (HC-DeflA, ß = 5.95), HC peak distance (HC-PD, ß = 2.57), deformation amplitude ratio max (DA Rmax, ß = -0.36), Ambrósio's relational thickness to the horizontal profile (ARTh, ß = 0.002). For axial length / corneal radius ratio, only A1v (ß = -2.01), A1 deflection amplitude (A1DeflA, ß = 2.30), HC-DeflA (ß = 1.49), HC-PD (ß = -0.21), DA Rmax (ß = 0.07), stress-strain index (SSI, ß = -0.29), ARTh (ß < 0.001) were significant associates. A1v (ß = 23.18), HC-DeflA (ß = -15.36), HC-PD (ß = 1.27), DA Rmax (ß = -0.66), SSI (ß = 3.53), ARTh (ß = -0.02) were significantly associated with spherical equivalent. CONCLUSION: Myopic eyes were more likely to have more deformable corneas and corneas in high myopia were easier to deform and were even softer compared with those in the mild/moderate myopia.

Distribution and determinants of corneal volume among healthy young Chinese adults: a cross-sectional study.

BACKGROUND: Several studies have previously reported the normal values of corneal volume (CV) in various populations, whereas little is known about the CV distribution in healthy young Chinese adults. Our study aimed to investigate the distribution of CV and its relationships with other ocular biometric parameters among healthy young Chinese adults. METHODS: A total of 1645 eyes from 1645 students at Dali University in Yunnan Province, China, were analyzed. Pentacam was used to measure CV. Central corneal thickness (CCT) and biomechanically corrected intraocular pressure (bIOP) were evaluated by Corvis-ST. Other biometrical parameters, including axial length (AL), keratometry, and white-to-white (WTW) distance, were measured using IOL Master. RESULTS: The mean age of the study population was 19.01 ± 0.92 years, and 68.81% of them were women. The CV was normally distributed in the whole sample, with a mean value of 61.23 ± 3.22 mm3. CV and CCT were significantly smaller in the Yi ethnic group than in the Han ethnic group (p < 0.01). CCT (coefficient: 0.085; p < 0.001) and keratometry (coefficient: 0.422; p < 0.001) were positively correlated with CV, while AL (coefficient: -0.204; p < 0.001), WTW distance (coefficient: -0.236; p < 0.001) and bIOP (coefficient: -0.06; p < 0.001) were inversely associated with CV. CONCLUSIONS: Our study provides an age-specific distribution of CV among healthy young Chinese adults. CCT, keratometry, AL, WTW distance and bIOP were important factors associated with CV.

IRON MAN interacts with BRUTUS to maintain iron homeostasis in Arabidopsis.

IRON MAN (IMA) peptides, a family of small peptides, control iron (Fe) transport in plants, but their roles in Fe signaling remain unclear. BRUTUS (BTS) is a potential Fe sensor that negatively regulates Fe homeostasis by promoting the ubiquitin-mediated degradation of bHLH105 and bHLH115, two positive regulators of the Fe deficiency response. Here, we show that IMA peptides interact with BTS. The C-terminal parts of IMA peptides contain a conserved BTS interaction domain (BID) that is responsible for their interaction with the C terminus of BTS. Arabidopsis thaliana plants constitutively expressing IMA genes phenocopy the bts-2 mutant. Moreover, IMA peptides are ubiquitinated and degraded by BTS. bHLH105 and bHLH115 also share a BID, which accounts for their interaction with BTS. IMA peptides compete with bHLH105/bHLH115 for interaction with BTS, thereby inhibiting the degradation of these transcription factors by BTS. Genetic analyses suggest that bHLH105/bHLH115 and IMA3 have additive roles and function downstream of BTS. Moreover, the transcription of both BTS and IMA3 is activated directly by bHLH105 and bHLH115 under Fe-deficient conditions. Our findings provide a conceptual framework for understanding the regulation of Fe homeostasis: IMA peptides protect bHLH105/bHLH115 from degradation by sequestering BTS, thereby activating the Fe deficiency response.

Identification of hyperthermophilic D-allulose 3-epimerase from Thermotoga sp. and its application as a high-performance biocatalyst for D-allulose synthesis.

D-Allulose 3-epimerase (DAE) is a vital biocatalyst for the industrial synthesis of D-allulose, an ultra-low calorie rare sugar. However, limited thermostability of DAEs hinders their use at high-temperature production. In this research, hyperthermophilic TI-DAE (Tm = 98.4 ± 0.7 ℃) from Thermotoga sp. was identified via in silico screening. A comparative study of the structure and function of site-directed saturation mutagenesis mutants pinpointed the residue I100 as pivotal in maintaining the high-temperature activity and thermostability of TI-DAE. Employing TI-DAE as a biocatalyst, D-allulose was produced from D-fructose with a conversion rate of 32.5%. Moreover, TI-DAE demonstrated excellent catalytic synergy with glucose isomerase CAGI, enabling the one-step conversion of D-glucose to D-allulose with a conversion rate of 21.6%. This study offers a promising resource for the enzyme engineering of DAEs and a high-performance biocatalyst for industrial D-allulose production.

OsIRO3 negatively regulates Fe homeostasis by repressing the expression of OsIRO2.

Iron (Fe) is crucial for crop productivity and quality. However, Fe deficiency is prevalent worldwide, particularly in alkaline soil. Plants have evolved sophisticated mechanisms to withstand Fe-deficient conditions. Oryza sativa IRON-RELATED BHLH TRANSCRIPTION FACTOR 3 (OsIRO3/OsbHLH63) has been identified as a negative regulator of Fe deficiency response signaling; however, the underlying mechanism remains unclear. In the present study, we constructed two iro3 mutants, which developed leaves with necrotic lesions under Fe-deficient conditions. Loss-of-function of OsIRO3 caused upregulation of Fe deficiency-associated genes in the root. Fe concentration measurements showed that the iro3 mutants had increased shoot Fe concentration only under Fe-deficient conditions. Further analysis revealed that OsIRO3 directly regulated the expression of IRON-RELATED BHLH TRANSCRIPTION FACTOR 2 (OsIRO2), which encodes a positive regulator of the Fe uptake system. Further investigation demonstrated that OsIRO3 interacted with POSITIVE REGULATOR OF IRON HOMEOSTASIS 1(OsPRI1) and OsPRI2, and. OsIRO3 repressed their transcription activation towards OsIRO2. OsIRO3 contains an EAR motif, which recruits the TOPLESS/TOPLESS-RELATED (OsTPL/OsTPRs) corepressors. Mutation of the EAR motif attenuated the repression ability of OsIRO3. This work sheds light on the molecular mechanism by which OsIRO3 modulates Fe homeostasis in rice.

Fe deficiency-induced ethylene synthesis confers resistance to Botrytis cinerea.

Although iron (Fe) deficiency is an adverse condition to growth and development of plants, it increases the resistance to pathogens. How Fe deficiency induces the resistance to pathogens is still unclear. Here, we reveal that the inoculation of Botrytis cinerea activates the Fe deficiency response of plants, which further induces ethylene synthesis and then resistance to B. cinerea. FIT and bHLH Ib are a pair of bHLH transcription factors, which control the Fe deficiency response. Both the Fe deficiency-induced ethylene synthesis and resistance are blocked in fit-2 and bhlh4x-1 (a quadruple mutant for four bHLH Ib members). SAM1 and SAM2, two ethylene synthesis-associated genes, are induced by Fe deficiency in a FIT-bHLH Ib-dependent manner. Moreover, SAM1 and SAM2 are required for the increased ethylene and resistance to B. cinerea under Fe-deficient conditions. Our findings suggest that the FIT-bHLH Ib module activates the expression of SAM1 and SAM2, thereby inducing ethylene synthesis and resistance to B. cinerea. This study uncovers that Fe signaling also functions as a part of the plant immune system against pathogens.

bHLH11 inhibits bHLH IVc proteins by recruiting the TOPLESS/TOPLESS-RELATED corepressors.

Iron (Fe) homeostasis is essential for plant growth and development. Many transcription factors (TFs) play pivotal roles in the maintenance of Fe homeostasis. bHLH11 is a negative TF that regulates Fe homeostasis. However, the underlying molecular mechanism remains elusive. Here, we generated two loss-of-function bhlh11 mutants in Arabidopsis (Arabidopsis thaliana), which display enhanced sensitivity to excess Fe, increased Fe accumulation, and elevated expression of Fe deficiency responsive genes. Levels of bHLH11 protein, localized in both the cytoplasm and nucleus, decreased in response to Fe deficiency. Co-expression assays indicated that bHLH IVc TFs (bHLH34, bHLH104, bHLH105, and bHLH115) facilitate the nuclear accumulation of bHLH11. Further analysis indicated that bHLH11 represses the transactivity of bHLH IVc TFs toward bHLH Ib genes (bHLH38, bHLH39, bHLH100, and bHLH101). The two ethylene response factor-associated amphiphilic repression motifs of bHLH11 provided the repression function by recruiting the TOPLESS/TOPLESS-RELATED (TPL/TPRs) corepressors. Correspondingly, the expression of Fe uptake genes increased in the tpr1 tpr4 tpl mutant. Moreover, genetic analysis revealed that bHLH11 has functions independent of FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR. This study provides insights into the complicated Fe homeostasis signaling network.

The transcription factor POPEYE negatively regulates the expression of bHLH Ib genes to maintain iron homeostasis.

Iron (Fe) is an essential trace element for plants. When suffering from Fe deficiency, plants modulate the expression of Fe deficiency-responsive genes to promote Fe uptake. POPEYE (PYE) is a key bHLH (basic helix-loop-helix) transcription factor involved in Fe homeostasis. However, the molecular mechanism of PYE regulating the Fe deficiency response remains elusive in Arabidopsis. We found that the overexpression of PYE attenuates the expression of Fe deficiency-responsive genes. PYE directly represses the transcription of bHLH Ib genes (bHLH38, bHLH39, bHLH100, and bHLH101) by associating with their promoters. Although PYE contains an ethylene response factor-associated amphiphilic repression (EAR) motif, it does not interact with the transcriptional co-repressors TOPLESS/TOPLESS-RELATED (TPL/TPRs). Sub-cellular localization analysis indicated that PYE localizes in both the cytoplasm and nucleus. PYE contains a nuclear export signal (NES) which is required for the cytoplasmic localization of PYE. Mutation of the NES amplifies the repression function of PYE, resulting in down-regulation of Fe deficiency-responsive genes. Co-expression assays indicated that three bHLH IVc members (bHLH104, bHLH105/ILR3, and bHLH115) facilitate the nuclear accumulation of PYE. Conversely, PYE indirectly represses the transcription activation ability of bHLH IVc. Additionally, PYE directly negatively regulates its own transcription. This study provides new insights into the Fe deficiency response signalling pathway and enhances the understanding of PYE functions in Arabidopsis.

Identification of high-risk patterns of myopia in Chinese students based on four major behavioral risk factors: a latent class analysis.

BACKGROUND: Myopia is prevalent in children and adolescents. Understanding the effect of multiple behaviors and their latent patterns on ocular biometric parameters may help clinicians and public health practitioners understand the behavioral risk pattern of myopia from a person-centered perspective. The purpose of this study was to identify the patterns of four major behavioral risk factors associated with myopia, including time spent outdoors, digital screen time, sleep duration, and performance of Chinese eye exercises. The study also examined the relationships between these behavioral patterns and myopia as well as ocular biometric parameters in a sample of Chinese college students. METHODS: This study included 2014 students from the Dali University Students Eye Health Study. The average age of the subjects was 19.0 ± 0.9 years old, ranging from 15.7 to 25.1 years old. Each participant's refractive status was measured using an autorefractor without cycloplegia and ocular biometric parameters were measured using an IOL Master. Behavioral risk factors were collected using a pre-designed self-administered questionnaire. Latent class analysis (LCA) was performed to identify cluster patterns of various behaviors. RESULTS: The prevalence of myopia was 91.8% in this population. The 2-class model was selected for the LCA based on goodness-of-fit evaluation metrics. Among the overall study sample, 41.1% and 58.9% were assigned into the high-risk and low-risk class, respectively. The risk of myopia [odds ratio (OR) = 2.12, 95% confidence interval (CI) = 1.52-3.14], high myopia (OR = 1.43, 95% CI = 1.14-1.78) and axial length/corneal radius (AL/CR) ratio of more than 3.0 (OR = 1.82, 95% CI = 1.22-2.72) were significantly higher in the high-risk compared with low-risk class. CONCLUSIONS: Chinese university students showed differential risks of myopia and could be subdivided into high- and low-risk clusters based on four behavioral variables.

Multiplex modification of Yarrowia lipolytica for enhanced erythritol biosynthesis from glycerol through modularized metabolic engineering.

Erythritol is a novelty 4-carbon sugar polyol and has great potential to be used as the precursor of some platform chemicals. The increasing cost of glucose poses researchers shifting insights to the cheaper biodiesel raw materials. Herein, we engineered a non-degradation, non-byproducts Yarrowia lipolytica for the erythritol production with high-titer from glycerol. Initially, the degradation and competition modules were blocked by URA3 counter-selection marker. Subsequently, a shortened biosynthetic pathway was explored to elevate its synthetic flux by multi-modules combination expression of functional genes. Furthermore, a screened glycerol transporter ScFPS1 was integrated into ERY6 genome to promote the glycerol uptake. The constructed strain ERY8 produced 176.66 g/L erythritol in the 5-L bioreactor with a yield and productivity of 0.631 g/g and 1.23 g/L/h, respectively, which achieved the highest fermentation production efficiency till date. This study proposed a novel multi-modules combination strategy for effectively engineering Y. lipolytica to produce erythritol using glycerol.

Malicious Traffic Identification with Self-Supervised Contrastive Learning.

As the demand for Internet access increases, malicious traffic on the Internet has soared also. In view of the fact that the existing malicious-traffic-identification methods suffer from low accuracy, this paper proposes a malicious-traffic-identification method based on contrastive learning. The proposed method is able to overcome the shortcomings of traditional methods that rely on labeled samples and is able to learn data feature representations carrying semantic information from unlabeled data, thus improving the model accuracy. In this paper, a new malicious traffic feature extraction model based on a Transformer is proposed. Employing a self-attention mechanism, the proposed feature extraction model can extract the bytes features of malicious traffic by performing calculations on the malicious traffic, thereby realizing the efficient identification of malicious traffic. In addition, a bidirectional GLSTM is introduced to extract the timing features of malicious traffic. The experimental results show that the proposed method is superior to the latest published methods in terms of accuracy and F1 score.

Sleep quality as a mediator of the relationship between screen time and negative emotions among Chinese college freshmen.

College freshmen are special populations facing great challenges in adapting to the brand new environment, and their lifestyle and emotional states are worthy of attention. Especially during the COVID-19 pandemic, their screen time and prevalence of negative emotions were significantly increased, but few studies have focused on such situation of college freshmen and illustrated relevant mechanisms. Thus, based on a sample of Chinese college freshmen during the COVID-19 pandemic, the current study aimed to investigate the association between their screen time and negative emotions (depression, anxiety and stress), and further explore the mediating effects of sleep quality. Data from 2,014 college freshmen was analyzed. The screen time was self-reported by participants using predesigned questionnaires. The Pittsburgh Sleep Quality Index (PSQI) and Chinese Version of Depression Anxiety and Stress Scale-21 (DASS-21) were used to assess sleep quality and emotional states, respectively. The mediation analysis was conducted to examine the meditation effect. Results indicated that participants with negative emotions tended to have longer daily screen time and worse sleep quality, sleep quality partially mediated the association between screen time and negative emotions.The critical role of sleep quality and related intervention measures should be recognized and implemented.

Fluorescence Enhancement of a Metal-Organic Framework for Ultra-Efficient Detection of Trace Benzene Vapor.

Indoor detection of volatile organic compounds (VOCs) concentration is necessary due to the serious toxicity hazards even at trace level. However, physisorbents usually exhibit weak interactions especially in the presence of trace concentrations of VOCs, thus exhibiting poor responsive signal. Herein, we report a new flexible metal-organic framework (MOF) that exhibits interesting pore-opening behavior after immersing in H2 O. The pore-opening phase shows significant (≈116 folds) and extremely fast (<1 minute) fluorescence enhancement after being exposed to saturated benzene vapor. The limit of detection concentration for benzene vapor can be calculated as 0.133 mg L-1 . Thus this material represents the first MOF to achieve visual detection of trace benzene vapor by the naked eyes. Theoretical calculations and single-crystal structure reveal that the special "bilateral π-π stacking" interactions between the host and guest, which facilitate electron transfer and greatly enhance the intensity of fluorescence.

TREM2 knockdown improves the therapeutic effect of PD-1 blockade in hepatocellular carcinoma.

Triggering receptor expressed on myeloid cells 2 (TREM2), which is typically expressed in microglia/macrophage, is a crucial receptor modulating the activation of immune cells. Recent single-cell RNA sequencing studies of the tumor microenvironment (TME) have found that TREM2 is highly expressed in several subgroups of tumor-associated macrophages (TAMs) with immunosuppressive activity. TREM2 knockout mice are more resistant to tumor growth than wild-type mice in multiple mice tumor models. But the function of TREM2 expression in TAMs of hepatocellular carcinoma (HCC) is still unclear. Here we used a self-complementary adeno-associated virus (scAAV) with macrophage tropism to efficiently knockdown TREM2 in TAMs in vivo and found that the growth of hepatocellular carcinoma was suppressed by TREM2 knockdown. Moreover, we found that TREM2 knockdown remodeled TAMs to an immune-stimulating status and enhanced the therapeutic effect of PD-1 immune-checkpoint blockade in HCC.

IRONMAN peptide interacts with OsHRZ1 and OsHRZ2 to maintain Fe homeostasis in rice.

IRONMAN (IMA) is a family of small peptides which positively regulate plant responses under Fe deficiency. However, the molecular mechanism by which OsIMA1 and OsIMA2 regulate Fe homeostasis in rice is unclear. Here, we reveal that OsIMA1 and OsIMA2 interact with the potential Fe sensors, OsHRZ1 (HAEMERYTHRIN MOTIF-CONTAINING REALLY INTERESTING NEW GENE (RING) AND ZINC-FINGER PROTEIN 1) and OsHRZ2. OsIMA1 and OsIMA2 contain a conserved 17 amino acid C-terminal region which is responsible for the interactions with OsHRZ1 and OsHRZ2. Plants overexpressing OsIMA1 (OsIMA1ox) show increased Fe concentration in seeds and reduced fertility, as observed in the hrz1-2 loss-of-function mutant plants. Moreover, the expression patterns of Fe deficiency inducible genes in the OsIMA1ox plants are the same as those in hrz1-2. Co-expression assays suggest that OsHRZ1 and OsHRZ2 promote the degradation of OsIMA1 proteins. As the interaction partners of OsHRZ1, the OsPRI (POSITIVE REGULATOR OF IRON HOMEOSTASIS) proteins also interact with OsHRZ2. The conserved C-terminal region of four OsPRIs contributes to the interactions with OsHRZ1 and OsHRZ2. An artificial IMA (aIMA) derived from the C-terminal of OsPRI1 can be also degraded by OsHRZ1. Moreover, aIMA overexpressing rice plants accumulate more Fe without reduction of fertility. This work establishes the link between OsIMAs and OsHRZs, and develops a new strategy for Fe fortification in rice.

CITF1 Functions Downstream of SPL7 to Specifically Regulate Cu Uptake in Arabidopsis.

Copper (Cu) is one of the most indispensable micronutrients, and proper Cu homeostasis is required for plants to maintain essential cellular functions. Plants activate the Cu uptake system during Cu limitation. Although SPL7 (SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 7) and CITF1 (Cu-DEFICIENCY INDUCED TRANSCRIPTION FACTOR 1) are two transcription factors in Cu homeostasis, it remains unclear how SPL7 and CITF1 control the Cu uptake system. Here, we reveal that overexpression of CITF1 causes the enhanced tolerance to Cu deficiency and the elevated expression of Cu uptake genes COPT2, FRO4 and FRO5. Electrophoretic mobility shift assays (EMSA) and transient expression assays indicate that SPL7 directly binds to and activates the promoter of CITF1. The overexpression of CITF1 partially rescues the sensitivity of spl7-1 to Cu deficiency. Transcriptome data suggest that SPL7 and CITF1 coregulate the Cu-homeostasis-signaling network, and CITF1 has its own independent functions. Moreover, both SPL7 and CITF1 can directly bind to and activate the promoters of three Cu uptake genes COPT2, FRO4 and FRO5. This work shows the functions of CITF1 in the Cu-homeostasis-signaling network, providing insights into the complicated molecular mechanism underlying Cu homeostasis.

FIT and bHLH Ib transcription factors modulate iron and copper crosstalk in Arabidopsis.

Although the crosstalk between iron (Fe) and copper (Cu) homeostasis signalling networks exists in plants, the underlined molecular mechanism remains unclear. FIT (FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR) and four bHLH Ib members (bHLH38, bHLH39, bHLH100 and bHLH101) are the key regulators of Fe homeostasis. Here, we reveal that FIT and bHLH Ib control the up-regulation of Cu-uptake genes (COPT2, FRO4 and FRO5) by Fe deficiency, and Cu is required for improving plant growth under Fe-deficiency conditions. The induction of Cu-uptake gene expression and the elevation of Cu concentration are inhibited in the fit-2 or bhlh4x (the quadruple mutant of four bHLH Ib genes) under Fe-deficiency conditions. The dual overexpression of both bHLH38 (or bHLH39) and FIT activates the expression of COPT2, FRO4 and FRO5 and increases Cu accumulation. Furthermore, bHLH Ib proteins directly bind to the promoters of COPT2, FRO4 and FRO5. Either Cu supplement or overexpression of COPT2 or FRO4 improves the growth of fit-2 under Fe-deficiency conditions. Moreover, the induction of COPT2, FRO4 and FRO5 by Fe deficiency is independent of SPL7, a central regulator of Cu-deficiency responses. This work through the link between bHLH Ib/FIT and COPT2/FRO4/FRO5 under Fe-deficiency conditions establishes a new relationship between Cu and Fe homeostasis.