Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

Proteomic analysis of ferroptosis pathways reveals a role of CEPT1 in suppressing ferroptosis.

Ferroptosis has been recognized as a unique cell death modality driven by excessive lipid peroxidation and unbalanced cellular metabolism. In this study, we established a protein interaction landscape for ferroptosis pathways through proteomic analyses, and identified choline/ethanolamine phosphotransferase 1 (CEPT1) as a lysophosphatidylcholine acyltransferase 3 (LPCAT3)-interacting protein that regulates LPCAT3 protein stability. In contrast to its known role in promoting phospholipid synthesis, we showed that CEPT1 suppresses ferroptosis potentially by interacting with phospholipases and breaking down certain pro-ferroptotic polyunsaturated fatty acid (PUFA)-containing phospholipids. Together, our study reveals a previously unrecognized role of CEPT1 in suppressing ferroptosis.

BRCA1-mediated dual regulation of ferroptosis exposes a vulnerability to GPX4 and PARP co-inhibition in BRCA1-deficient cancers.

Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i co-treatment. Finally, we show that xenograft tumors derived from BRCA1-mutant breast cancer patients with PARPi resistance exhibit decreased GPX4 expression and high sensitivity to PARP and GPX4 co-inhibition. Our results show that BRCA1 deficiency induces a ferroptosis vulnerability to PARP and GPX4 co-inhibition and inform a therapeutic strategy for overcoming PARPi resistance in BRCA1-deficient cancers.

Hydrogen Impact: A Review on Diffusibility, Embrittlement Mechanisms, and Characterization.

Hydrogen embrittlement (HE) is a broadly recognized phenomenon in metallic materials. If not well understood and managed, HE may lead to catastrophic environmental failures in vessels containing hydrogen, such as pipelines and storage tanks. HE can affect the mechanical properties of materials such as ductility, toughness, and strength, mainly through the interaction between metal defects and hydrogen. Various phenomena such as hydrogen adsorption, hydrogen diffusion, and hydrogen interactions with intrinsic trapping sites like dislocations, voids, grain boundaries, and oxide/matrix interfaces are involved in this process. It is important to understand HE mechanisms to develop effective hydrogen resistant strategies. Tensile, double cantilever beam, bent beam, and fatigue tests are among the most common techniques employed to study HE. This article reviews hydrogen diffusion behavior, mechanisms, and characterization techniques.

IlNRAMP5 is required for cadmium accumulation and the growth in Iris lactea under cadmium exposures.

Iris lactea is potentially applied for remediating Cd-contaminated soils due to the strong ability of Cd uptake and accumulation. However, its molecular mechanism underlying Cd uptake pathway remains unknown. Here, we report a member of NRAMP (Natural Resistance-Associated Macrophage Protein) family, IlNRAMP5, is involved in Cd/Mn uptake and the growth in I. lactea response to Cd. IlNRAMP5 was localized onto the plasma membrane, and was induced by Cd. It was expressed in the root cortex rather than the central vasculature, and in leaf vascular bundle and mesophyll cells. Heterologous expression in yeast showed that IlNRAMP5 could transport Cd and Mn, but not Fe. Knockdown of IlNRAMP5 triggered a significant reduction in Cd uptake, further diminishing the accumulation of Cd. In addition, silencing IlNRAMP5 disrupted Mn homeostasis by lowering Mn uptake and Mn allocation, accompanied by remarkably inhibiting photosynthesis under Cd conditions. Overall, the findings suggest that IlNRAMP5 plays versatile roles in Cd accumulation by mediating Cd uptake, and contributes to maintain the growth via modulating Mn homeostasis in I. lactea under Cd exposures. This would provide a mechanistic understanding Cd phytoremediation efficiency in planta.

CircFam190a: a critical positive regulator of osteoclast differentiation via enhancement of the AKT1/HSP90ß complex.

The identification of key regulatory factors that control osteoclastogenesis is important. Accumulating evidence indicates that circular RNAs (circRNAs) are discrete functional entities. However, the complexities of circRNA expression as well as the extent of their regulatory functions during osteoclastogenesis have yet to be revealed. Here, based on circular RNA sequencing data, we identified a circular RNA, circFam190a, as a critical regulator of osteoclast differentiation and function. During osteoclastogenesis, circFam190a is significantly upregulated. In vitro, circFam190a enhanced osteoclast formation and function. In vivo, overexpression of circFam190a induced significant bone loss, while knockdown of circFam190a prevented pathological bone loss in an ovariectomized (OVX) mouse osteoporosis model. Mechanistically, our data suggest that circFam90a enhances the binding of AKT1 and HSP90ß, promoting AKT1 stability. Altogether, our findings highlight the critical role of circFam190a as a positive regulator of osteoclastogenesis, and targeting circFam190a might be a promising therapeutic strategy for treating pathological bone loss.

Hypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development.

Hypoxia-induced adenosine creates an immunosuppressive tumor microenvironment (TME) and dampens the efficacy of immune checkpoint inhibitors (ICIs). We found that hypoxia-inducible factor 1 (HIF-1) orchestrates adenosine efflux through two steps in hepatocellular carcinoma (HCC). First, HIF-1 activates transcriptional repressor MXI1, which inhibits adenosine kinase (ADK), resulting in the failure of adenosine phosphorylation to adenosine monophosphate. This leads to adenosine accumulation in hypoxic cancer cells. Second, HIF-1 transcriptionally activates equilibrative nucleoside transporter 4, pumping adenosine into the interstitial space of HCC, elevating extracellular adenosine levels. Multiple in vitro assays demonstrated the immunosuppressive role of adenosine on T cells and myeloid cells. Knockout of ADK in vivo skewed intratumoral immune cells to protumorigenic and promoted tumor progression. Therapeutically, combination treatment of adenosine receptor antagonists and anti-PD-1 prolonged survival of HCC-bearing mice. We illustrated the dual role of hypoxia in establishing an adenosine-mediated immunosuppressive TME and offered a potential therapeutic approach that synergizes with ICIs in HCC.

Short-term clinical effects and inflammatory response of natural orifice specimen extraction surgery versus conventional laparoscopic-assisted surgery for the treatment of sigmoid and rectal cancer.

Background: The clinical outcomes and benefits of natural orifice specimen extraction surgery (NOSES) in colorectal cancer have not been fully evaluated comparing to conventional laparoscopic-assisted radical resection. This retrospective study was conducted to investigate the short-term clinical benefits of NOSES versus conventional laparoscopic-assisted surgery for the treatment of sigmoid and rectal cancer. Methods: A total of 112 patients with sigmoid or rectal cancer were included in this retrospective study. The observation group (n=60) was treated with NOSES, and the control group (n=52) was treated with conventional laparoscopic-assisted radical resection. Following these interventions, the postoperative recovery and inflammatory response indexes were compared between the two groups. Results: In contrast with the control group, the observation group significantly had longer operation time (t=2.83, P=0.006), but shorter durations for the resumption of a semi-liquid diet (t=2.17, P=0.032), and length of postoperative hospital stay (t=2.74, P=0.007), as well as fewer postoperative incision infections (χ2=7.32, P=0.009). Moreover, the levels of immunoglobulin (Ig), including IgG (t=2.29, P=0.024), IgA (t=3.30, P=0.001), and IgM (t=3.38, P=0.001), in the observation group were markedly higher than those within the control group at 3 days postoperatively. Also, the levels of inflammatory indicators including interleukin (IL)-6 (t=4.22, P=5.02E-5), C-reactive protein (CRP) (t=3.73, P=3.5E-4), and tumor necrosis factor (TNF)-α (t=2.94, P=0.004) in the observation group were considerably lower than those in the control group at 3 days after the operation. Conclusions: NOSES can improve the postoperative recovery and has benefits in reducing the inflammatory response than conventional laparoscopic-assisted surgery.

A dielectric electrolyte composite with high lithium-ion conductivity for high-voltage solid-state lithium metal batteries.

The ionic conductivity of composite solid-state electrolytes does not meet the application requirements of solid-state lithium (Li) metal batteries owing to the harsh space charge layer of different phases and low concentration of movable Li+. Herein, we propose a robust strategy for creating high-throughput Li+ transport pathways by coupling the ceramic dielectric and electrolyte to overcome the low ionic conductivity challenge of composite solid-state electrolytes. A highly conductive and dielectric composite solid-state electrolyte is constructed by compositing the poly(vinylidene difluoride) matrix and the BaTiO3-Li0.33La0.56TiO3-x nanowires with a side-by-side heterojunction structure (PVBL). The polarized dielectric BaTiO3 greatly promotes the dissociation of Li salt to produce more movable Li+, which locally and spontaneously transfers across the interface to coupled Li0.33La0.56TiO3-x for highly efficient transport. The BaTiO3-Li0.33La0.56TiO3-x effectively restrains the formation of the space charge layer with poly(vinylidene difluoride). These coupling effects contribute to a quite high ionic conductivity (8.2 × 10-4 S cm-1) and lithium transference number (0.57) of the PVBL at 25 °C. The PVBL also homogenizes the interfacial electric field with electrodes. The LiNi0.8Co0.1Mn0.1O2/PVBL/Li solid-state batteries stably cycle 1,500 times at a current density of 180 mA g-1, and pouch batteries also exhibit an excellent electrochemical and safety performance.

Ferroptosis Suppressor Protein 1 Inhibition Promotes Tumor Ferroptosis and Anti-tumor Immune Responses in Liver Cancer.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with dreadful clinical outcome. Tyrosine kinase inhibitors and immune checkpoint inhibitors are the only United States Food and Drug Administration-approved therapeutic options for patients with advanced HCC with limited therapeutic success. Ferroptosis is a form of immunogenic and regulated cell death caused by chain reaction of iron-dependent lipid peroxidation. Coenzyme Q10 (CoQ10)/ferroptosis suppressor protein 1 (FSP1) axis was recently identified as a novel protective mechanism against ferroptosis. We would like to explore whether FSP1 could be a potential therapeutic target for HCC. METHODS: FSP1 expression in human HCC and paired non-tumorous tissue samples were determined by reverse transcription-quantitative polymerase chain reaction, followed by clinicopathologic correlation and survival studies. Regulatory mechanism for FSP1 was determined using chromatin immunoprecipitation. The hydrodynamic tail vein injection model was used for HCC induction to evaluate the efficacy of FSP1 inhibitor (iFSP1) in vivo. Single-cell RNA sequencing revealed the immunomodulatory effects of iFSP1 treatment. RESULTS: We showed that HCC cells greatly rely on the CoQ10/FSP1 system to overcome ferroptosis. We found that FSP1 was significantly overexpressed in human HCC and is regulated by kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 pathway. FSP1 inhibitor iFSP1 effectively reduced HCC burden and profoundly increased immune infiltrates including dendritic cells, macrophages, and T cells. We also demonstrated that iFSP1 worked synergistically with immunotherapies to suppress HCC progression. CONCLUSIONS: We identified FSP1 as a novel, vulnerable therapeutic target in HCC. The inhibition of FSP1 potently induced ferroptosis, which promoted innate and adaptive anti-tumor immune responses and effectively suppressed HCC tumor growth. FSP1 inhibition therefore represents a new therapeutic strategy for HCC.

Inhibiting Formation and Reduction of Li2 CO3 to LiCx at Grain Boundaries in Garnet Electrolytes to Prevent Li Penetration.

Poor ion and high electron transport at the grain boundaries (GBs) of ceramic electrolytes are the primary reasons for lithium filament infiltration and short-circuiting of all-solid-state lithium metal batteries (ASLMBs). Herein, it is discovered that Li2 CO3 at the GBs of Li7 La3 Zr2 O12 (LLZO) sheets is reduced to highly electron-conductive LiCx during cycling, resulting in lithium penetration of LLZO. The ionic and electronic conductivity of the GBs within LLZO can be simultaneously tuned using sintered Li3 AlF6 . The generated LiAlO2 (LAO) infusion and F-doping at the GBs of LLZO (LAO-LLZOF) significantly reduce the Li2 CO3 content and broaden the energy bandgap of LLZO, which decreases the electronic conductivity of LAO-LLZOF. LAO forms a 3D continuous ion transport network at the GB that significantly improves the total ionic conductivity. Lithium penetration within LLZO is suppressed and an all-solid-state LiFePO4 /LAO-LLZOF/Li battery stably cycled for 5500 cycles at 3 C. This work reveals the chemistry of Li2 CO3 at the LLZO GBs during cycling, presents a novel lithium penetration mechanism within garnet electrolytes, and provides an innovative method to simultaneously regulate the ion and electron transport at the GBs in garnet electrodes for advanced ASLMBs.

MNX1-AS1, a c-Myc induced lncRNA, promotes the Warburg effect by regulating PKM2 nuclear translocation.

BACKGROUND: Altered glycolysis is the most fundamental metabolic change associated with the Warburg effect. Some glycolytic enzymes such as PKM2, the dominant pyruvate kinase in cancer cells, have been shown to engage in non-glycolytic functions that contribute to tumor metabolism. However, the precise mechanisms are not completely understood. METHODS: The role of MNX1-AS1 in hepatocellular carcinoma progression was assessed both in vitro and in vivo. Northern blotting, RNA pulldown, mass spectrometry, RNA-binding protein immunoprecipitation, ChIP, luciferase reporter assays, RNA FISH and immunofluorescence staining were used to explore the detail molecular mechanism of MNX1-AS1 in hepatocellular carcinoma (HCC). RESULTS: Here we dissect how MNX1-AS1, a long non-coding RNA (lncRNA), reinforces the Warburg effect through facilitating the non-glycolytic actions of PKM2 in the cell nucleus. We found that MNX1-AS1 expression was frequently overexpressed in HCC-derived cell lines and tissues compared to their normal hepatic cell counterparts, a finding consistent with its status as pan-cancer expressed lncRNA. In the context of HCC, we show MNX1-AS1 acts as a scaffold to promote interactions between PKM2 and importin α5. In response to EGFR activation, the resulting ternary complex drives the translocation of PKM2 into the nucleus. In consequence, glycolytic pathway components including key mediators of the Warburg effect (LDHA, GLUT1 and PDK1) are upregulated though the coactivator function of PKM2. Manipulating MNX1-AS1 elicited robust effects on glycolysis associated with marked changes in HCC growth in vitro and in xenograft models, indicative of the significant contribution of MNX1-AS1 to tumorigenic phenotypes. Moreover, while MNX1-AS1 expression is driven by c-Myc, its actions associated with PKM2 were shown to be downstream and independent of c-Myc. CONCLUSIONS: Given the status of MNX1-AS1 as a pan-cancer upregulated lncRNA, this implicitly highlights the potential of targeting MNX1-AS1 to selectively counter the Warburg effect in a range of tumor types.

circPRKAA1 activates a Ku80/Ku70/SREBP-1 axis driving de novo fatty acid synthesis in cancer cells.

Many metabolism-related genes undergo alternative splicing to generate circular RNAs, but their functions remain poorly understood. Here we report that circPRKAA1, a circular RNA (circRNA) derived from the α1 subunit of AMP-activated protein kinase (AMPK), fulfills a fundamental role in maintaining lipid homeostasis. circPRKAA1 expression facilitates fatty acid synthesis and promotes lipid storage through two coordinated functions. First, circPRKAA1 promotes a tetrameric complex between the Ku80/Ku70 heterodimer and the mature form of sterol regulatory element-binding protein 1 (mSREBP-1) to enhance the stability of mSREBP-1. Second, circPRKAA1 selectively binds to the promoters of the ACC1, ACLY, SCD1, and FASN genes to recruit mSREBP-1, upregulating their transcription and increasing fatty acid synthesis to promote cancer growth. circPRKAA1 biogenesis is negatively regulated by AMPK activity, with lower AMPK activation in hepatocellular carcinoma tissue frequently associated with elevated circPRKAA1 expression. This work identifies circPRKAA1 as an integral element of AMPK-regulated reprogramming of lipid metabolism in cancer cells.

KCTD9 inhibits the Wnt/ß-catenin pathway by decreasing the level of ß-catenin in colorectal cancer.

Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide. However, the molecular mechanisms underlying CRC progression remain to be further defined to improve patient outcomes. In this study, we found that KCTD9, a member of the potassium channel tetramerization domain-containing (KCTD) gene family, was commonly downregulated in CRC tissues and that KCTD9 expression was negatively correlated with the clinical CRC stage. Survival analysis showed that patients whose tumors expressed low KCTD9 levels had poorer outcomes. Functional analyses revealed that KCTD9 overexpression inhibited CRC cell proliferation and metastasis, whereas KCTD9 knockdown promoted CRC cell proliferation and metastasis in both in vitro and in vivo models. Manipulating KCTD9 levels in CRC cells via overexpression or knockdown showed KCTD9 expression positively influenced the degradation of ß-catenin levels leading to inhibition of Wnt signaling and reductions in Wnt pathway target gene expression. Mechanistically, we found KCTD9 associated with ZNT9 (Zinc Transporter 9), a coactivator of ß-catenin-mediated gene transcription. The overexpression of KCTD9 or knockdown of ZNT9 in CRC cells increased the polyubiquitination and proteasomal degradation of ß-catenin. In turn, the KCTD9-ZNT9 interaction disrupted interactions between ß-catenin and ZNT9, thereby leading to decreased ß-catenin target gene expression and the inhibition of Wnt signaling. In conclusion, our findings propose that KCTD9 functions as a tumor suppressor that inhibits CRC cell proliferation and metastasis by inactivating the Wnt/ß-catenin pathway. Moreover, its frequent downregulation in CRC suggests KCTD9 as a potential prognostic and therapeutic target in CRC.

Disclosing the Origin of Irreversible Sodiation-Desodiation of a Cu4SnP10 Nanowire Anode by Ex Situ Transmission Electron Microscopy.

Cu4SnP10, a promising phosphide material for sodium-ion battery anode applications, suffers from poor cycling stability, and its mechanism remains unclear. This is largely due to the amorphous nature of the active materials upon cycling and its possible structural change at a small length scale (e.g., nanometers), making it difficult to access the phase/structural evolution of the electrode. In the present work, we show that the phase/structural change of the Cu4SnP10 nanowire electrode can be systematically investigated using a comprehensive set of ex situ transmission electron microscopy-based techniques, which are ideal for decay mechanism analysis of electrode materials of amorphous nature and with nanoscale structural evolution. The compositional elements of Cu4SnP10 nanowires are found to be spatially redistributed at a nanometer scale upon the initial sodiation, and this is partially reversible in the following desodiation process. Damage accumulates until a critical size of phase separation/segregation is reached, when the active material loss takes place, leading to fast deterioration of the entire Cu4SnP10 nanowire structure and thus its electrochemical performance. The phase segregation driven-active material loss is found to dominate the cycle-dependent capacity decay of the Cu4SnP10 nanowire electrode.

Self-Healing Mechanism of Lithium in Lithium Metal.

Li is an ideal anode material for use in state-of-the-art secondary batteries. However, Li-dendrite growth is a safety concern and results in low coulombic efficiency, which significantly restricts the commercial application of Li secondary batteries. Unfortunately, the Li-deposition (growth) mechanism is poorly understood on the atomic scale. Here, machine learning is used to construct a Li potential model with quantum-mechanical computational accuracy. Molecular dynamics simulations in this study with this model reveal two self-healing mechanisms in a large Li-metal system, viz. surface self-healing, and bulk self-healing. It is concluded that self-healing occurs rapidly in nanoscale; thus, minimizing the voids between the Li grains using several comprehensive methods can effectively facilitate the formation of dendrite-free Li.

Point-to-point trajectory planning for space robots based on jerk constraints.

This paper studies the Cartesian point-to-point optimal trajectory planning for space robots oriented to space maintenance operations. Aiming at the problems of poor stability, large base disturbance, and large joint variation in the motion planning of point-to-point maintenance in space, a planning method is proposed to minimize the base disturbance and the total joint angle variation under the jerk constraint on the premise of ensuring the accuracy of the end pose. First, the attitude of the space robot is described by the unit quaternion, and the velocity relationship between the joint angle, the end effector, and the base posture is introduced. Then, the joint trajectories were parameterized by a fifth degree polynomial, and a trajectory planning model with the minimum perturbation of the base and the minimum variation of the joint of the manipulator was established under the condition that the end effector satisfied the pose and the jerk constraint. Finally, a multi-objective optimization algorithm is proposed to deal with the trajectory optimization problem under nonlinear constraints. The simulation results show that the proposed trajectory planning method can optimize the base attitude and joint angle of the space manipulator under the premise of the optimal trajectory and stability of the terminal execution tool, which ensures the stability of the space robot's on-orbit service and reduces the energy consumption.

High-Energy and High-Power Pseudocapacitor-Battery Hybrid Sodium-Ion Capacitor with Na+ Intercalation Pseudocapacitance Anode.

High-performance and low-cost sodium-ion capacitors (SICs) show tremendous potential applications in public transport and grid energy storage. However, conventional SICs are limited by the low specific capacity, poor rate capability, and low initial coulombic efficiency (ICE) of anode materials. Herein, we report layered iron vanadate (Fe5V15O39 (OH)9·9H2O) ultrathin nanosheets with a thickness of ~ 2.2 nm (FeVO UNSs) as a novel anode for rapid and reversible sodium-ion storage. According to in situ synchrotron X-ray diffractions and electrochemical analysis, the storage mechanism of FeVO UNSs anode is Na+ intercalation pseudocapacitance under a safe potential window. The FeVO UNSs anode delivers high ICE (93.86%), high reversible capacity (292 mAh g-1), excellent cycling stability, and remarkable rate capability. Furthermore, a pseudocapacitor-battery hybrid SIC (PBH-SIC) consisting of pseudocapacitor-type FeVO UNSs anode and battery-type Na3(VO)2(PO4)2F cathode is assembled with the elimination of presodiation treatments. The PBH-SIC involves faradaic reaction on both cathode and anode materials, delivering a high energy density of 126 Wh kg-1 at 91 W kg-1, a high power density of 7.6 kW kg-1 with an energy density of 43 Wh kg-1, and 9000 stable cycles. The tunable vanadate materials with high-performance Na+ intercalation pseudocapacitance provide a direction for developing next-generation high-energy capacitors.

Universal Approach to Fabricating Graphene-Supported Single-Atom Catalysts from Doped ZnO Solid Solutions.

Single-atom catalysts (SACs) have attracted widespread interest for many catalytic applications because of their distinguishing properties. However, general and scalable synthesis of efficient SACs remains significantly challenging, which limits their applications. Here we report an efficient and universal approach to fabricating a series of high-content metal atoms anchored into hollow nitrogen-doped graphene frameworks (M-N-Grs; M represents Fe, Co, Ni, Cu, etc.) at gram-scale. The highly compatible doped ZnO templates, acting as the dispersants of targeted metal heteroatoms, can react with the incoming gaseous organic ligands to form doped metal-organic framework thin shells, whose composition determines the heteroatom species and contents in M-N-Grs. We achieved over 1.2 atom % (5.85 wt %) metal loading content, superior oxygen reduction activity over commercial Pt/C catalyst, and a very high diffusion-limiting current (6.82 mA cm-2). Both experimental analyses and theoretical calculations reveal the oxygen reduction activity sequence of M-N-Grs. Additionally, the superior performance in Fe-N-Gr is mainly attributed to its unique electron structure, rich exposed active sites, and robust hollow framework. This synthesis strategy will stimulate the rapid development of SACs for diverse energy-related fields.