The OsCPK17-OsPUB12-OsRLCK176 module regulates immune homeostasis in rice.

Plant immunity is fine-tuned to balance growth and defense. However, little is yet known about molecular mechanisms underlying immune homeostasis in rice (Oryza sativa). In this study, we reveal that a rice calcium-dependent protein kinase (CDPK), OsCPK17, interacts with and stabilizes the receptor-like cytoplasmic kinase (RLCK) OsRLCK176, a close homolog of Arabidopsis thaliana BOTRYTIS-INDUCED KINASE 1 (AtBIK1). Oxidative burst and pathogenesis-related gene expression triggered by pathogen-associated molecular patterns are significantly attenuated in the oscpk17 mutant. The oscpk17 mutant and OsCPK17-silenced lines are more susceptible to bacterial diseases than the wild-type plants, indicating that OsCPK17 positively regulates rice immunity. Furthermore, the plant U-box (PUB) protein OsPUB12 ubiquitinates and degrades OsRLCK176. OsCPK17 phosphorylates OsRLCK176 at Ser83, which prevents the ubiquitination of OsRLCK176 by OsPUB12 and thereby enhances the stability and immune function of OsRLCK176. The phenotypes of the ospub12 mutant in defense responses and disease resistance show that OsPUB12 negatively regulates rice immunity. Therefore, OsCPK17 and OsPUB12 reciprocally maintain OsRLCK176 homeostasis and function as positive and negative immune regulators, respectively. This study uncovers positive cross talk between CDPK- and RLCK-mediated immune signaling in plants and reveals that OsCPK17, OsPUB12, and OsRLCK176 maintain rice immune homeostasis.

Ustilaginoidea virens secretes a family of phosphatases that stabilize the negative immune regulator OsMPK6 and suppress plant immunity.

Rice false smut caused by Ustilaginoidea virens is emerging as a devastating disease of rice (Oryza sativa) worldwide; however, the molecular mechanisms underlying U. virens virulence and pathogenicity remain largely unknown. Here we demonstrate that the small cysteine-rich secreted protein SCRE6 in U. virens is translocated into host cells during infection as a virulence factor. Knockout of SCRE6 leads to attenuated U. virens virulence to rice. SCRE6 and its homologs in U. virens function as a novel family of mitogen-activated protein kinase phosphatases harboring no canonical phosphatase motif. SCRE6 interacts with and dephosphorylates the negative immune regulator OsMPK6 in rice, thus enhancing its stability and suppressing plant immunity. Ectopic expression of SCRE6 in transgenic rice promotes pathogen infection by suppressing the host immune responses. Our results reveal a previously unidentified fungal infection strategy in which the pathogen deploys a family of tyrosine phosphatases to stabilize a negative immune regulator in the host plant to facilitate its infection.

LAPTM5 mediates immature B cell apoptosis and B cell tolerance by regulating the WWP2-PTEN-AKT pathway.

Elimination of autoreactive developing B cells is an important mechanism to prevent autoantibody production. However, how B cell receptor (BCR) signaling triggers apoptosis of immature B cells remains poorly understood. We show that BCR stimulation up-regulates the expression of the lysosomal-associated transmembrane protein 5 (LAPTM5), which in turn triggers apoptosis of immature B cells through two pathways. LAPTM5 causes BCR internalization, resulting in decreased phosphorylation of SYK and ERK. In addition, LAPTM5 targets the E3 ubiquitin ligase WWP2 for lysosomal degradation, resulting in the accumulation of its substrate PTEN. Elevated PTEN levels suppress AKT phosphorylation, leading to increased FOXO1 expression and up-regulation of the cell cycle inhibitor p27Kip1 and the proapoptotic molecule BIM. In vivo, LAPTM5 is involved in the elimination of autoreactive B cells and its deficiency exacerbates autoantibody production. Our results reveal a previously unidentified mechanism that contributes to immature B cell apoptosis and B cell tolerance.

SAMHD1-mediated dNTP degradation is required for efficient DNA repair during antibody class switch recombination.

Sterile alpha motif and histidine-aspartic acid domain-containing protein 1 (SAMHD1), a dNTP triphosphohydrolase, regulates the levels of cellular dNTPs through their hydrolysis. SAMHD1 protects cells from invading viruses that depend on dNTPs to replicate and is frequently mutated in cancers and Aicardi-Goutières syndrome, a hereditary autoimmune encephalopathy. We discovered that SAMHD1 localizes at the immunoglobulin (Ig) switch region, and serves as a novel DNA repair regulator of Ig class switch recombination (CSR). Depletion of SAMHD1 impaired not only CSR but also IgH/c-Myc translocation. Consistently, we could inhibit these two processes by elevating the cellular nucleotide pool. A high frequency of nucleotide insertion at the break-point junctions is a notable feature in SAMHD1 deficiency during activation-induced cytidine deaminase-mediated genomic instability. Interestingly, CSR induced by staggered but not blunt, double-stranded DNA breaks was impaired by SAMHD1 depletion, which was accompanied by enhanced nucleotide insertions at recombination junctions. We propose that SAMHD1-mediated dNTP balance regulates dNTP-sensitive DNA end-processing enzyme and promotes CSR and aberrant genomic rearrangements by suppressing the insertional DNA repair pathway.

A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections.

RHOH, an atypical small GTPase predominantly expressed in hematopoietic cells, plays a vital role in immune function. A deficiency in RHOH has been linked to epidermodysplasia verruciformis, lung disease, Burkitt lymphoma and T cell defects. Here, we report a novel germline homozygous RHOH c.245G > A (p.Cys82Tyr) variant in a 21-year-old male suffering from recurrent, invasive, opportunistic infections affecting the lungs, eyes, and brain. His sister also succumbed to a lung infection during early adulthood. The patient exhibited a persistent decrease in CD4+ T, B, and NK cell counts, and hypoimmunoglobulinemia. The patient's T cell showed impaired activation upon in vitro TCR stimulation. In Jurkat T cells transduced with RHOHC82Y, a similar reduction in activation marker CD69 up-regulation was observed. Furthermore, the C82Y variant showed reduced RHOH protein expression and impaired interaction with the TCR signaling molecule ZAP70. Together, these data suggest that the newly identified autosomal-recessive RHOH variant is associated with T cell dysfunction and recurrent opportunistic infections, functioning as a hypomorph by disrupting ZAP70-mediated TCR signaling.

LiGa(IO3 )4 : An Excellent NLO Material with Unprecedented 2D [Ga(IO3 )4 ]∞ - Layer Synthesized by Aliovalent Substitution.

Nonlinear optical (NLO) crystals are indispensable for the solid-state lasers for their ability to expand wavelength spectral to the regions where the directing lasing is difficult or even impossible, yet the rational design of a high-performance NLO crystal remains a great challenge owing to the severe structural and properties' requirements. Herein, a new noncentrosymmetric (NCS) and polar gallium iodate, LiGa(IO3 )4 , with a novel 2D anionic layer, is successfully designed and synthesized by the aliovalent substitution strategy based on classic α-LiIO3 . The 2D [Ga(IO3 )4 ]∞ - layer in LiGa(IO3 )4 is built from the GaO6 octahedra and highly polarizable units IO3 . Compared with its parent compound, the partial replacement of A-site Li+ cation with main group Ga3+ cation facilitates LiGa(IO3 )4 to possess excellent NLO properties, including the large second-harmonic generation (SHG) response (14 × KH2 PO4 (KDP) @ 1064 nm), wide bandgap (4.25 eV), large birefringence (0.23 @ 1064 nm), and wide optical transparency from UV to mid-IR. These reveal that LiGa(IO3 )4 will be a promising NLO crystal.

Temperature-Induced Reversible Photoluminescence Switching and Ultraviolet-Pumped Light-Emitting Diode Applications of a Perovskite (C6H10N2)2MnCl6·2H2O Crystal.

Zero-dimensional (0D) organic-inorganic hybrid halides present many fascinating photophysical properties for promising optoelectronic applications such as light-emitting diodes (LEDs), X-ray imaging, photodetectors, and anticounterfeiting. Herein, a centimeter-sized single crystal (C6H10N2)2MnCl6·2H2O with a 0D perovskite structure was obtained via a solvent evaporation method. A bright red emission at 618 nm with a larger Stokes shift of more than 300 nm and a long fluorescence lifetime of 6.21 ms were measured. Notably, a reversible PL switching from red emission to nonluminescence has been presented in the cycles of heating-cooling processes from RT to 100 °C. Furthermore, the temperature-induced luminescence shows a quick recovery after 20 conversion cycles, exhibiting excellent stability and temperature sensing. According to the structural and theoretical analyses, the temperature-induced luminescence is primarily due to hydrogen-bonding interactions between (MnCl6)4- and H2O molecules. Particularly, a temperature anticounterfeiting application has been designed based on its reversible temperature-dependent PL switching. Importantly, the ultraviolet-pumped LEDs fabricated by (C6H10N2)2MnCl6·2H2O single crystals are perfectly achieved. Anyway, this work clearly demonstrates that 0D Mn-based perovskite with temperature-dependent PL switching greatly extends its potential applications in electro-optical display, temperature sensing, and anticounterfeiting devices.

From NaGa(IO3)3F to NaGa(IO3)2F2 and NaGa(IO3)4: The Effects of Chemical Substitution between F- Anions and IO3- Groups on the Structures and Properties of Gallium Iodates.

Introducing F- anions or substituting F- anions with IO3- groups has been proven to be ideal strategies for designing novel noncentrosymmetric (NCS) and polar materials, yet systematic investigation into the effect of F- anions or the substitution of IO3- for F- anions on structures and properties remains rarely explored. Herein, two new gallium iodates, NaGa(IO3)2F2 (1) and NaGa(IO3)4 (2), were successfully designed and synthesized based on NaGa(IO3)3F by introducing more F- anions and replacing F- anions with IO3 groups, respectively. Structurally, in compound 1, the adjacent [GaF3(IO3)3]3- polyanions are connected in an antiparallel manner, resulting in a complete cancellation of local polarity. While in compound 2, all IO3 groups in 2D [Ga(IO3)4]∞- layers are aligned, leading to large macroscopic polarization. Additionally, chemical substitution also results in a qualitative improvement in the functional properties of compound 2. It possesses strong SHG response (12 × KDP @1064 nm) and broad optical transparency, coupled with large birefringence (0.21 @1064 nm), showcasing its promise as a promising nonlinear optical (NLO) crystal. The effects of chemical substitution between F- anions and IO3- groups on the structures and properties are discussed in detail.

Pb3[O10Pb20](SiO4)4X10 (X = Cl, Br): The First Pb-Containing Halogen Silicates with Mirror-Symmetric Pseudo-Aurivillius Bilayers.

Two new congruently melting Pb-containing halogen silicates, Pb3[O10Pb20](SiO4)4X10 (X = Cl, Br), have been synthesized using a high-temperature solution method. Their crystal structures were determined by single-crystal X-ray diffraction, and both compounds crystallize in the orthorhombic space group Cmca. In both structures, the mirror-symmetric bilayer composed of Pb-O polyhedra is observed for the first time in Pb-containing silicates and belongs to α-PbO derivatives and is related to the Aurivillius phase. Thermal behavior analysis, UV-vis diffuse-reflectance spectroscopy, and IR spectroscopy were also performed. The Pb3[O10Pb20](SiO4)4Cl10 matrix was doped with Eu3+ ions as a dopant, and its potential application in fluorescence was confirmed from the resulting orange-red emission.

Ultra-Broad-Band-Excitable Cu-Based Halide (C4H10N)4Cu4I8 with High Stability for LED Applications.

Currently, organic-inorganic hybrid cuprous-based halides are receiving substantial attention for their eco-friendliness, distinctive structures, and outstanding photophysical properties. Nevertheless, most of the reported cuprous-based halides demand deep ultraviolet excitation with a narrow excitation range that can meet the commercial requirement. Herein, zero-dimensional (0D) cuprous-based halide (C4H10N)4Cu4I8 single crystals (SCs) were synthesized, with an ultrabroad band excitation ranging 260-450 nm and a greenish-yellow emission band peaking at 560 nm. Excitingly, (C4H10N)4Cu4I8 also features a large Stokes shift of 300 nm, a high photoluminescence quantum yield (PLQY) of up to 84.66%, and a long lifetime of 137 µs. Furthermore, density functional theory calculations were performed to explore the relationship between structure and photophysical properties, and the photoluminescence performance of (C4H10N)4Cu4I8 originates from the electron interactions in [Cu2I4]2- clusters. Taking advantage of broad band excitation and excellent photoluminescent performances, a high luminescence characteristic UV-pumped light-emitting diode (LED) device with remarkable color stability was fabricated by employing the as-synthesized (C4H10N)4Cu4I8 SCs, which present the promising applications of low-dimensional cuprous-based halides in solid-state lighting.

APIP5 functions as a transcription factor and an RNA-binding protein to modulate cell death and immunity in rice.

Many transcription factors (TFs) in animals bind to both DNA and mRNA, regulating transcription and mRNA turnover. However, whether plant TFs function at both the transcriptional and post-transcriptional levels remains unknown. The rice (Oryza sativa) bZIP TF AVRPIZ-T-INTERACTING PROTEIN 5 (APIP5) negatively regulates programmed cell death and blast resistance and is targeted by the effector AvrPiz-t of the blast fungus Magnaporthe oryzae. We demonstrate that the nuclear localization signal of APIP5 is essential for APIP5-mediated suppression of cell death and blast resistance. APIP5 directly targets two genes that positively regulate blast resistance: the cell wall-associated kinase gene OsWAK5 and the cytochrome P450 gene CYP72A1. APIP5 inhibits OsWAK5 expression and thus limits lignin accumulation; moreover, APIP5 inhibits CYP72A1 expression and thus limits reactive oxygen species production and defense compounds accumulation. Remarkably, APIP5 acts as an RNA-binding protein to regulate mRNA turnover of the cell death- and defense-related genes OsLSD1 and OsRac1. Therefore, APIP5 plays dual roles, acting as TF to regulate gene expression in the nucleus and as an RNA-binding protein to regulate mRNA turnover in the cytoplasm, a previously unidentified regulatory mechanism of plant TFs at the transcriptional and post-transcriptional levels.

Genetic association between smoking and DLCO in idiopathic pulmonary fibrosis patients.

BACKGROUND: Observational studies have shown that smoking is related to the diffusing capacity of the lungs for carbon monoxide (DLCO) in individuals with idiopathic pulmonary fibrosis (IPF). Nevertheless, further investigation is needed to determine the causal effect between these two variables. Therefore, we conducted a study to investigate the causal relationship between smoking and DLCO in IPF patients using two-sample Mendelian randomization (MR) analysis. METHODS: Large-scale genome-wide association study (GWAS) datasets from individuals of European descent were analysed. These datasets included published lifetime smoking index (LSI) data for 462,690 participants and DLCO data for 975 IPF patients. The inverse-variance weighting (IVW) method was the main method used in our analysis. Sensitivity analyses were performed by MR‒Egger regression, Cochran's Q test, the leave-one-out test and the MR-PRESSO global test. RESULTS: A genetically predicted increase in LSI was associated with a decrease in DLCO in IPF patients [ORIVW = 0.54; 95% CI 0.32-0.93; P = 0.02]. CONCLUSIONS: Our study suggested that smoking is associated with a decrease in DLCO. Patients diagnosed with IPF should adopt an active and healthy lifestyle, especially by quitting smoking, which may be effective at slowing the progression of IPF.

Assembly of π-Conjugated [B3O6] Units by Mer-Isomer [YO3F3] Octahedra to Design a UV Nonlinear Optical Material, Cs2YB3O6F2.

Achieving the extreme balance of the key performance requirements is the crucial to breakthrough the application bottleneck for nonlinear optical (NLO) materials. Herein, by assembly of the π-conjugated [B3O6] functional species with the aid of structure-directing property of mer-isomer [YO3F3] octahedra, a new ultraviolet (UV) NLO material, Cs2YB3O6F2 with aligned arrangement of coplanar [B3O6] groups has been synthesized. The polar material exhibits the rare coexistence of the largest second harmonic generation response of 5.6×KDP, the largest birefringence of 0.091 at 532 nm, the shortest Type I phase-matching down to 200.5 nm and deep-ultraviolet transparency among reported acentric rare-earth borates with [B3O6] groups. Remarkably, benefiting from the enhanced bonding force among functional units [B3O6], a firm three-dimensional framework is constructed, which facilitates the growth of large crystals. This can be proved by a block shape crystal with dimensional of 6×5×4 mm3, indicating that it was a promising UV NLO crystal. This work provides a powerful strategy to design UV NLO materials with good performances.

Cs3In(In4Se7)(P2Se6): A Multi-Chromophore Chalcogenide with Excellent Nonlinear Optical Property Designed by Group Grafting.

Non-centrosymmetric (NCS) and polar materials capable of exhibiting many important functional properties are indispensable for electro-optical technologies, yet their rational structural design remains a significant challenge. Here, we report a "group grafting" strategy for designing the first multi-chromophore selenophosphate, Cs3In(In4Se7)(P2Se6), that crystallizes in a NCS and polar space group of Cm. The structure features a unique basic building unit (BBU) [In(In4Se10)(P2Se6)], formed through "grafting [In4Se10] supertetrahedra on the root of [In(P2Se6)2] groups". Theoretical calculations confirm that this [In(In4Se10)(P2Se6)] BBU can achieve a "1+1>2" combination of properties from two chromophores, [In4Se10] supertetrahedron and ethane-like [P2Se6] dimer. That makes Cs3In(In4Se7)(P2Se6) exhibit excellent linear and nonlinear optical (NLO) properties, including a strong second harmonic generation (SHG) response (~6×AgGaS2), a large band gap (2.45 eV), broad infrared (IR) transmission (up to 19.5 µm), a significant birefringence (0.26 @1064 nm) as well as the congruently-melting property at ~700 °C. Therefore, Cs3In(In4Se7)(P2Se6) will be a promising NLO crystal, especially in the IR region, and this research also demonstrates that "group grafting" will be an effective strategy for constructing novel polar BBUs with multi-chromophore to design NCS structures and high-performance IR NLO materials.

Cs3[(BOP)2(B3O7)3]: A Deep-Ultraviolet Nonlinear Optical Crystal Designed by Optimizing Matching of Cation and Anion Groups.

Deep-ultraviolet nonlinear optical (DUV NLO) crystals are indispensable for solid-state lasers to produce coherent light with wavelengths shorter than 200 nm, yet their structure design still faces great challenges because two groups of conflicting properties must be satisfied simultaneously, i.e., "large second harmonic generation (SHG) response-large band gap" and "large birefringence-weak growth anisotropy". Clearly, hitherto, no crystal can perfectly satisfy these properties, including KBe2BO3F2. Herein, we design a new mixed-coordinated borophosphate Cs3[(BOP)2(B3O7)3] (CBPO) by optimizing the matching of cation and anion groups, which unprecedentedly achieves a balance for two groups of contradictions concurrently for the first time. In the structure of CBPO, it has the coplanar and π-conjugated B3O7 groups, which can make it possess a large SHG response (3 × KDP) and large birefringence (0.075@532 nm). Then, terminal O atoms of these B3O7 groups are connected by BO4 and PO4 tetrahedra, which eliminates all dangling bonds and blue shifts the UV absorption edge to the DUV region (165 nm). More importantly, owing to the judicious selection of cations, the size of cations and void of anion groups is a perfect match, which makes CBPO possess a very stable three-dimensional anion framework and thus reduces the crystal growth anisotropy. A CBPO single crystal with a size of up to 20 × 17 × 8 mm3 has been successfully grown, through which a DUV coherent light has also been achieved in Be-free DUV NLO crystals for the first time. These indicate CBPO will be the next generation of DUV NLO crystals.

[Ba4 (S2 )][ZnGa4 S10 ]: Design of an Unprecedented Infrared Nonlinear Salt-Inclusion Chalcogenide with Disulfide-Bonds.

Salt-inclusion chalcogenides (SICs) have been receiving widespread attention due to their large second harmonic generation (SHG) responses and wide bandgaps, however most of them suffer from small birefringence limiting their technical application. Herein, by introducing the π-conjugated (S2 )2- units in the ionic guest of salt-inclusion structure, the first disulfide-bond-containing SIC, [Ba4 (S2 )][ZnGa4 S10 ] has been synthesized. It exhibits the widest bandgap up to 3.39 eV among polychalcogenides and strong SHG response as large as that of AgGaS2 (AGS). Importantly, its birefringence reaches a max value of 0.053@1064 nm among AGS-like SICs, indicating it is a promising IR nonlinear optical (NLO) material. Theoretical calculations reveal that the π-conjugated (S2 )2- units and covalent GaS layers favor the enhanced birefringence and large SHG response. This work provides not only a new type of SIC for the first time, but also new lights on the design of IR NLO materials.

Glia maturation factor-γ is involved in S1P-induced marginal zone B-cell chemotaxis and optimal IgM production to type II T-independent antigen.

Marginal zone B cells (MZBs) represent a unique B-cell sub-population that rapidly differentiate into IgM-secreting plasma cells in response to T-independent (T-I) antigen. Sphingosine 1-phosphate (S1P) promotes MZB localization to the marginal zone. However, intracellular molecules involved in MZB localization and migration remain largely unknown. Here, we show that MZBs lacking the glia maturation factor-γ (GMFG) are impaired in chemotaxis toward S1P under both in vitro and in vivo conditions, suggesting that GMFG is an effector downstream of S1P receptors. GMFG undergoes serine phosphorylation upon S1P stimulation and is required for S1P-induced desensitization of S1P receptor 1 (S1PR1). Compared with wild-type mice, Gmfg-/- mice produce elevated levels of 4-hydroxy-3-nitrophenyl-acetyl (NP)-specific IgM against a T-I type II antigen, NP-Ficoll, accompanied by dysregulated MZB localization. These results identify GMFG as a regulator of S1P-induced MZB chemotaxis and reveal a role for MZB localization in the marginal zone for optimal IgM production against a T-I antigen.

Alignment of Λ-Shaped Basic Building Units to Construct One New KMoO3(IO3) Polar Polymorph.

Nonlinear optical (NLO) crystals assume an irreplaceable role in the development of laser science and technologies, yet the reasonable design of a high-performance NLO crystal remains difficult owing to the unpredictability of inorganic structures. In this research, we report the fourth polymorph of KMoO3(IO3), i.e., δ-KMoO3(IO3), to understand the effect of different packing patterns of basic building units on structures and properties. Among four polymorphs of KMoO3(IO3), the different stacking patterns of Λ-shaped cis-MoO4(IO3)2 units result in α- and ß-KMoO3(IO3) featuring nonpolar layered structures, whereas γ- and δ-KMoO3(IO3) display polar frameworks. Theoretical calculations and structure analysis reveal that IO3 units can be regarded as the main source of its polarization in δ-KMoO3(IO3). Further property measurements show that δ-KMoO3(IO3) exhibits a large second-harmonic generation response (6.6 × KDP), a wide band gap (3.34 eV), and a broad mid-infrared transparency region (∼10 µm), which demonstrates that adjusting the arrangement of the Λ-shaped basic building units is an effective approach for rationally designing NLO crystals.

Phosphates with Two Types of Isolated P-O Groups: Noncentrosymmetric Na6Sr2Bi3(PO4)(P2O7)4 and Centrosymmetric Cs2CaBi2(PO4)2(P2O7).

Inorganic phosphates are of great interest, because of their rich structural chemistry and multiple functional properties. Compared with the phosphates that only contain the solely condensed P-O groups, the phosphates with various condensed P-O groups are less reported, especially for the noncentrosymmetric (NCS) ones. Here, two new bismuth phosphates, Na6Sr2Bi3(PO4)(P2O7)4 and Cs2CaBi2(PO4)2(P2O7), were synthesized by the solid-state reaction and both structures contain two types of isolated P-O groups. Remarkably, Na6Sr2Bi3(PO4)(P2O7)4 crystallizes in the tetragonal space group P4̅21c, which represents the first NCS bismuth phosphate with PO4 and P2O7 groups. Detailed structural comparisons among Bi3+-containing alkali/alkaline-earth metal phosphates show that the ratios of cations/phosphorus profoundly influence the condensed degree of P-O groups. Ultraviolet-visible-near-infrared (UV-vis-NIR) diffusion spectra show that both compounds have the relatively short UV cutoff edges. And Na6Sr2Bi3(PO4)(P2O7)4 has a second-harmonic generation response of 1.1 × KDP. The first-principles calculations are carried out to understand the structure-performance relationship.

FOXN4 affects myocardial ischemia-reperfusion injury through HIF-1α/MMP2-mediated ferroptosis of cardiomyocytes.

Myocardial ischemia-reperfusion injury (MIRI) is an important factor leading to myocardial injury and necrosis, and can induce ischemic heart disease. Forkhead box protein N4 (FOXN4) belongs to the gene family of Fork head domain (Fox) transcription factors and plays an important role in heart formation and function. However, whether FOXN4 is involved in MIRI progression is unknown. In this study, we investigated the clinicopathological significance and potential mechanisms of FOXN4 in MIRI. The expressions of FOXN4 and MMP2 were measured by quantitative reverse transcriptase polymerase chain reaction, apoptosis was detected by flow cytometry, and cell viability was detected by examining EdU incorporation into DNA. The signaling pathway related proteins FOXN4, MMP2, HIF-1α, apoptosis-related proteins Bcl-2 and Bax, and ferroptosis-related proteins TFR1 and IREB2 were detected by western blot, the levels of malondialdehyde (MDA), Fe2+, reactive oxygen species (ROS), and glutathione were detected by commercially available kits, and the cardiac histopathology after MIRI was evaluated by hematoxylin and eosin staining. We found that knockdown of FOXN4 alleviated oxidative stress, inhibited ROS production, and inhibited ferroptosis in MIR-injured tissues and cardiomyocytes. In addition, knockdown of FOXN4 inhibited myocardial injury, improved myocardial cell viability, restored myocardial function, and alleviated MIRI. We interrogated the mechanism and found that FOXN4 can enhance its binding to HIF-1α, up-regulate the expression of MMP2, and mediate ferroptosis to regulate the functional activity of cardiomyocytes to affect the progression of MIRI. This study provides new insights into the role of FOXN4 in MIRI progression and suggests that FOXN4 may represent a potential therapeutic target in MIRI progression by regulating the active function of cardiomyocytes through HIF-1α/MMP2-mediated ferroptosis.