Lineage Landscape: a comprehensive database that records lineage commitment across species.

Commitment to specific cell lineages is critical for mammalian embryonic development. Lineage determination, differentiation, maintenance, and organogenesis result in diverse life forms composed of multiple cell types. To understand the formation and maintenance of living individuals, including human beings, a comprehensive database that integrates multi-omic information underlying lineage differentiation across multiple species is urgently needed. Here, we construct Lineage Landscape, a database that compiles, analyzes and visualizes transcriptomic and epigenomic information related to lineage development in a collection of species. This landscape draws together datasets that capture the ongoing changes in cell lineages from classic model organisms to human beings throughout embryonic, fetal, adult, and aged stages, providing comprehensive, open-access information that is useful to researchers of a broad spectrum of life science disciplines. Lineage Landscape contains single-cell gene expression and bulk transcriptomic, DNA methylation, histone modifications, and chromatin accessibility profiles. Using this database, users can explore genes of interest that exhibit dynamic expression patterns at the transcriptional or epigenetic levels at different stages of lineage development. Lineage Landscape currently includes over 6.6 million cells, 15 million differentially expressed genes and 36 million data entries across 10 species and 34 organs. Lineage Landscape is free to access, browse, search, and download at http://data.iscr.ac.cn/lineage/#/home.

Light-Assisted Lithium Metal Anode Enabled by In Situ Photoelectrochemical Engineering.

Rechargeable battery devices with high energy density are highly demanded by the modern society. The use of lithium (Li) anodes is extremely attractive for future rechargeable battery devices. However, the notorious Li dendritic and instability of solid electrolyte interface (SEI) issues pose series of challenge for metal anodes. Here, based on the inspiration of in situ photoelectrochemical engineering, it is showed that a tailor-made composite photoanodes with good photoelectrochemical properties (Li affinity property and photocatalytic property) can significantly improve the electrochemical deposition behavior of Li anodes. The light-assisted Li anode is accommodated in the tailor-made current collector without uncontrollable Li dendrites. The as-prepared light-assisted Li metal anode can achieve the in situ stabilization of SEI layer under illumination. The corresponding in situ formation mechanism and photocatalytic mechanism of composite photoanodes are systematically investigated via DFT theoretical calculation, ex situ UV-vis and ex situ XPS characterization. It is worth mentioning that the as-prepared composite photoanodes can adapt to the ultra-high current density of 15 mA cm-2 and the cycle capacity of 15 mAh cm-2 under light, showing no dendritic morphology and low hysteresis voltage. This work is of great significance for the commercialization of new generation Li metal batteries.

An iPSC-derived exosome-pulsed dendritic cell vaccine boosts antitumor immunity in melanoma.

Induced pluripotent stem cells (iPSCs) express a broad spectrum of tumor-associated antigens and exert prophylactic effects on various tumors. However, some problems remain, such as potential tumorigenicity, challenges in transport to the lymph nodes and spleen, and limited antitumor effects. Thus, designing a safe and effective iPSC-based tumor vaccine is necessary. We prepared iPSC-derived exosomes and incubated them with DCs (dendritic cells) for pulsing to explore their antitumor effects in murine melanoma models. The antitumor immune response induced by the DC vaccine pulsed with iPSC exosomes (DC + EXO) was assessed in vitro and in vivo. After DC + EXO vaccination, extracted spleen T cells effectively killed a variety of tumor cells (melanoma, lung cancer, breast cancer, and colorectal cancer) in vitro. In addition, DC + EXO vaccination significantly inhibited melanoma growth and lung metastasis in mouse models. Furthermore, DC + EXO vaccination induced long-term T cell responses and prevented melanoma rechallenge. Finally, biocompatibility studies showed that the DC vaccine did not significantly alter the viability of normal cells and mouse viscera. Hence, our research may provide a prospective strategy of a safe and effective iPSC-based tumor vaccine for clinical use.

Photoelectrochemical Engineering for Light-Assisted Rechargeable Metal Batteries: Mechanism, Development, and Future.

Rechargeable battery devices with high energy density are highly demanded by  our  modern society. The use of metal anodes is extremely attractive for future rechargeable battery devices. However, the notorious metal dendritic and instability of solid electrolyte interface issues pose a series of challenges for metal anodes. Recently, considering the indigestible dynamical behavior of metal anodes, photoelectrochemical engineering of light-assisted metal anodes have been rapidly developed since they efficiently utilize the integration and synergy of oriented crystal engineering and photocatalysis engineering, which provided a potential way to unlock the interface electrochemical mechanism and deposition reaction kinetics of metal anodes. This review starts with the fundamentals of photoelectrochemical engineering and follows with the state-of-art advance of photoelectrochemical engineering for light-assisted rechargeable metal batteries where photoelectrode materials, working principles, types, and practical applications are explained. The last section summarizes the major challenges and some invigorating perspectives for future research on light-assisted rechargeable metal batteries.

Advance of Prussian Blue-Derived Nanohybrids in Energy Storage: Current Status and Perspective.

Great changes have occurred in the energy storage area in recent years as a result of rapid economic expansion. People have conducted substantial research on sustainable energy conversion and storage systems in order to mitigate the looming energy crisis. As a result, developing energy storage materials is critical. Materials with an open frame structure are known as Prussian blue analogs (PBAs). Anode materials for oxides, sulfides, selenides, phosphides, borides, and carbides have been extensively explored as anode materials in the field of energy conversion and storage in recent years. The advantages and disadvantages of oxides, sulfides, selenides, phosphides, borides, carbides, and other elements, as well as experimental methodologies and electrochemical properties, are discussed in this work. The findings reveal that employing oxides, sulfides, selenides, phosphides, borides, and other electrode materials to overcome the problems of low conductivity, excessive material loss, and low specific volume is ineffective. Therefore, this review intends to address the issues of diverse energy storage materials by combining multiple technologies to manufacture battery materials with low cost, large capacity, and extended service life.

Computational-Guided Design of Photoelectrode Active Materials for Light-Assisted Energy Storage.

The design of a novel photoelectric integrated system is considered to be an efficient way to utilize and store inexhaustible solar energy. However, the mechanism of photoelectrode under illuminate conditions is still unclear. Density functional theory (DFT) provides standardized analysis and becomes a powerful way to explain the photoelectrochemical mechanism. Herein, the feasibility of four metal oxide configurations as photoelectrode materials by using a high throughput calculation method based on DFT are investigated. According to the photoelectrochemical properties, band structure and density of states are calculated, and the intercalate/deintercalate simulation is performed with adsorption configuration. The calculation indicates that the band gap of Fe2 CoO4 (2.404 eV) is narrower than that of Co3 O4 (2.553 eV), as well as stronger adsorption energy (-3.293 eV). The relationship between the electronic structure and the photoelectrochemical performance is analyzed and verified according to the predicted DFT results by subsequent experiments. Results show that the Fe2 CoO4 photoelectrode samples exhibit higher coulombic efficiency (97.4%) than that under dark conditions (94.9%), which is consistent with the DFT results. This work provides a general method for the design of integrated photoelectrode materials and is expected to be enlightening for the adjustment of light-assisted properties of multifunctional materials.

The Molecular Biology of Prostate Cancer Stem Cells: From the Past to the Future.

Prostate cancer (PCa) continues to rank as the second leading cause of cancer-related mortality in western countries, despite the golden treatment using androgen deprivation therapy (ADT) or anti-androgen therapy. With decades of research, scientists have gradually realized that the existence of prostate cancer stem cells (PCSCs) successfully explains tumor recurrence, metastasis and therapeutic failure of PCa. Theoretically, eradication of this small population may improve the efficacy of current therapeutic approaches and prolong PCa survival. However, several characteristics of PCSCs make their diminishment extremely challenging: inherent resistance to anti-androgen and chemotherapy treatment, over-activation of the survival pathway, adaptation to tumor micro-environments, escape from immune attack and being easier to metastasize. For this end, a better understanding of PCSC biology at the molecular level will definitely inspire us to develop PCSC targeted approaches. In this review, we comprehensively summarize signaling pathways responsible for homeostatic regulation of PCSCs and discuss how to eliminate these fractional cells in clinical practice. Overall, this study deeply pinpoints PCSC biology at the molecular level and provides us some research perspectives.

A Powerful Chiral Super Brønsted C-H Acid for Asymmetric Catalysis.

A new type of chiral super Brønsted C-H acids, BINOL-derived phosphoryl bis((trifluoromethyl)sulfonyl) methanes (BPTMs), were developed. As compared to widely utilized BINOL-derived chiral phosphoric acids (BPAs) and N-triflyl phosphoramides (NTPAs), BPTMs displayed much higher Brønsted acidity, resulting in dramatically improved activity and excellent enantioselectivity as demonstrated in catalytic asymmetric Mukaiyama-Mannich reaction, allylic amination, three-component coupling of allyltrimethylsilane with 9-fluorenylmethyl carbamate and aldehydes, and protonation of silyl enol ether. These new strong Brønsted C-H acids have provided a platform for expanding the chemistry of asymmetric Brønsted acid catalysis.

Element-Doped Mxenes: Mechanism, Synthesis, and Applications.

Heteroatom doping can endow MXenes with various new or improved electromagnetic, physicochemical, optical, and structural properties. This greatly extends the arsenal of MXenes materials and their potential for a spectrum of applications. This article comprehensively and critically discusses the syntheses, properties, and emerging applications of the growing family of heteroatom-doped MXenes materials. First, the doping strategies, synthesis methods, and theoretical simulations of high-performance MXenes materials are summarized. In order to achieve high-performance MXenes materials, the mechanism of atomic element doping from three aspects of lattice optimization, functional substitution, and interface modification is analyzed and summarized, aiming to provide clues for developing new and controllable synthetic routes. The mechanisms underlying their advantageous uses for energy storage, catalysis, sensors, environmental purification and biomedicine are highlighted. Finally, future opportunities and challenges for the study and application of multifunctional high-performance MXenes are presented. This work could open up new prospects for the development of high-performance MXenes.

Integrated Photovoltaic Charging and Energy Storage Systems: Mechanism, Optimization, and Future.

As an emerging solar energy utilization technology, solar redox batteries (SPRBs) combine the superior advantages of photoelectrochemical (PEC) devices and redox batteries and are considered as alternative candidates for large-scale solar energy capture, conversion, and storage. In this review, a systematic summary from three aspects, including: dye sensitizers, PEC properties, and photoelectronic integrated systems, based on the characteristics of rechargeable batteries and the advantages of photovoltaic technology, is presented. The matching problem of high-performance dye sensitizers, strategies to improve the performance of photoelectrode PEC, and the working mechanism and structure design of multienergy photoelectronic integrated devices are mainly introduced and analyzed. In particular, the devices and improvement strategies of high-performance electrode materials are analyzed from the perspective of different photoelectronic integrated devices (liquid-based and solid-state-based). Finally, future perspectives are provided for further improving the performance of SPRBs. This work will open up new prospects for the development of high-efficiency photoelectronic integrated batteries.

Increased chemosensitivity via targeting testicular nuclear receptor 4 (TR4)-Oct4-interleukin 1 receptor antagonist (IL1Ra) axis in prostate cancer CD133+ stem/progenitor cells to battle prostate cancer.

Prostate cancer (PCa) stem/progenitor cells are known to have higher chemoresistance than non-stem/progenitor cells, but the underlying molecular mechanism remains unclear. We found the expression of testicular nuclear receptor 4 (TR4) is significantly higher in PCa CD133(+) stem/progenitor cells compared with CD133(-) non-stem/progenitor cells. Knockdown of TR4 levels in the established PCa stem/progenitor cells and the CD133(+) population of the C4-2 PCa cell line with lentiviral TR4 siRNA led to increased drug sensitivity to the two commonly used chemotherapeutic drugs, docetaxel and etoposide, judging from significantly reduced IC50 values and increased apoptosis in the TR4 knockdown cells. Mechanism dissection studies found that suppression of TR4 in these stem/progenitor cells led to down-regulation of Oct4 expression, which, in turn, down-regulated the IL-1 receptor antagonist (IL1Ra) expression. Neutralization experiments via adding these molecules into the TR4 knockdown PCa stem/progenitor cells reversed the chemoresistance, suggesting that the TR4-Oct4-IL1Ra axis may play a critical role in the development of chemoresistance in the PCa stem/progenitor cells. Together, these studies suggest that targeting TR4 may alter chemoresistance of PCa stem/progenitor cells, and this finding provides the possibility of targeting TR4 as a new and better approach to overcome the chemoresistance problem in PCa therapeutics.

Impact of COVID-19 emission reduction on dust aerosols and marine chlorophyll-a concentration.

The long-range transport of dust aerosols plays a crucial role in biogeochemical cycling, and dust deposition is an important source of nutrients for marine phytoplankton growth. To study the impact of COVID-19 emission reduction on dust aerosols and marine chlorophyll-a (Chl-a) concentration, we selected two similar dust processes from the COVID-19 period (10-15 March 2020) and the non-COVID-19 period (15-20 March 2019) using the Euclidean distance calculation method in combination with the HYSPLIT model and multiple satellite data. During the non-COVID-19 period, the proportion of dust was 6.68 %, approximately half that of the COVID-19 period. Meanwhile, the proportion of polluted dust during the non-COVID-19 period was 4.95 %, which was more than tenfold compared to the COVID-19 period. Furthermore, noticeable discrepancies in Chl-a concentration were observed between the two periods. In the non-COVID-19 period, the maximum daily deposition of dust aerosols can reach 16.23 mg/m2, resulting in a 39-85 % increase in Chl-a concentration. However, during COVID-19 period, the maximum daily dust deposition can reach 33.33 mg/m2, while the increase in Chl-a concentration was <30 %. This conclusion suggests that reductions in anthropogenic emissions during the COVID-19 period have influenced the nutrient content of dust aerosols, resulting in a lesser impact on Chl-a concentrations in the ocean.

Silencing circATXN1 in Aging Nucleus Pulposus Cell Alleviates Intervertebral Disc Degeneration via Correcting Progerin Mislocalization.

Circular RNAs (circRNAs) play a critical regulatory role in degenerative diseases; however, their functions and therapeutic applications in intervertebral disc degeneration (IVDD) have not been explored. Here, we identified that a novel circATXN1 highly accumulates in aging nucleus pulposus cells (NPCs) accountable for IVDD. CircATXN1 accelerates cellular senescence, disrupts extracellular matrix organization, and inhibits mitochondrial respiration. Mechanistically, circATXN1, regulated by heterogeneous nuclear ribonucleoprotein A2B1-mediated splicing circularization, promotes progerin translocation from the cell nucleus to the cytoplasm and inhibits the expression of insulin-like growth factor 1 receptor (IGF-1R). To demonstrate the therapeutic potential of circATXN1, siRNA targeting the backsplice junction of circATNX1 was screened and delivered by tetrahedral framework nucleic acids (tFNAs) due to their unique compositional and tetrahedral structural features. Our siRNA delivery system demonstrates superior abilities to transfect aging cells, clear intracellular ROS, and enhanced biological safety. Using siRNA-tFNAs to silence circATXN1, aging NPCs exhibit reduced mislocalization of progerin in the cytoplasm and up-regulation of IGF-1R, thereby demonstrating a rejuvenated cellular phenotype and improved mitochondrial function. In vivo, administering an aging cell-adapted siRNA nucleic acid framework delivery system to progerin pathologically expressed premature aging mice (zmpste24-/-) can ameliorate the cellular matrix in the nucleus pulposus tissue, effectively delaying IVDD. This study not only identified circATXN1 functioning as a cell senescence promoter in IVDD for the first time, but also successfully demonstrated its therapeutic potential via a tFNA-based siRNA delivery strategy.

Reconstruction of chronic anterior cruciate ligament rupture using the ligament advanced reinforcement system artificial ligament-comparisons between patients over 50 years and under 50 years.

Background: With the increasing physical activity level in elderly population, anterior cruciate ligament (ACL) injuries are becoming more frequent. Due to the possible surgery complications, treatment for ACL rupture in patients with advanced age is still controversial. The purpose of this study was to compare the therapeutic effects of reconstruction using the ligament advanced reinforcement system (LARS) artificial ligament in patients older than 50 and patients younger than 50 with chronic ACL rupture. Methods: Indications included: (I) concurrent history of subjective symptomatic anterior knee instability despite nonoperative rehabilitation for least 3 months, (II) positive preoperative Lachman and pivot shift tests, (III) ACL stump still connecting the femur with the tibia as demonstrated by Magnetic Resonance Imaging (MRI), and (IV) some residual ligament fibers still connecting the femur with the tibia as demonstrated by arthroscopy. Participants were divided into groups based on their age. Participants were divided into groups based on their age. A total of 37 patients who underwent reconstruction of chronic ACL rupture using the LARS artificial ligament were divided into group A (≥50 years, n=16) and group B (<50 years, n=21). Results: The outcome measures were compared between the 2 groups. These included the baseline clinical data, the International Knee Documentation Committee (IKDC) scoring system, Pivot shift test, Lachman test, Kneelax arthrometer measurements, Tegner activity scale, Lysholm knee scoring scale, and Kellgren-Lawrence radiographic classification of arthritis and complications. Postoperative knee laxity and the functional examination were significantly improved compared to preoperative measurements for both groups (all P<0.01). No significant differences were found in postoperative knee laxity and functional examination between the 2 groups (all P>0.05). The level of osteoarthritis did not statistically increase in either group during follow-up (all P>0.05). No complications associated with the arthroscopic surgery were found in either group. Conclusions: The reconstruction of chronic ACL rupture using the LARS artificial ligament showed similar therapeutic effects in patients over the age of 50 and those under the age of 50.

Androgen receptor suppresses lung cancer invasion and increases cisplatin response via decreasing TPD52 expression.

Lung cancer, as the most commonly diagnosed malignancy, still accounts for the leading cause of cancer-related deaths worldwide. The high rate of mortality and tumor recurrence has prompted clinicians and scientists to urgently explore new targets for improved treatment. Previous studies have indicated a potential role of the androgen receptor (AR) in the progression of non-small cell lung cancer (NSCLC). However, the precise mechanisms underlying this association, particularly its relation to TPD52-mediated cell invasion and cisplatin (DDP) response, have not been fully elucidated. Therefore, further investigation is necessary to gain a better understanding of these mechanisms and their potential implications for lung cancer treatment. In this study, we discovered that AR can suppress NSCLC cell invasion and increase cisplatin response by downregulating the expression of circular RNA (circRNA), specifically circ-SLCO1B7. This suppression is achieved through the direct binding of AR to the 5' promoter region of the host gene SLCO1B7. The decreased expression of circ-SLCO1B7, mediated by AR, released miR-139-5p back to the RISC (RNA induced silencing complex), where it bonds to the 3' untranslated region (3'UTR) of Tumor Protein D52 (TPD52) messenger RNA, resulting in TPD52 reduction. The in vivo data also validated the functional contribution of AR/circ-SLCO1B7/miR-139-5p/TPD52 axis to lung cancer progression. Furthermore, analysis of human NSCLC databases and clinical specimens confirmed the association of the AR/circ-SLCO1B7/miR-139-5p/TPD52 signaling pathway with NSCLC progression. Collectively, the results from our study suggest that AR can suppress lung cancer cell invasion and increase DDP response by modulating the circ-SLCO1B7/miR-139-5p/TPD52 signaling pathway. Targeting this novel signaling pathway may be a new therapeutic strategy to effectively constrain NSCLC development.

A Photo-rechargeable Aqueous Zinc-Tellurium Battery Enabled by the Janus-Jointed Perovskite/Te Photocathode.

The combination of photo-driven self-powered supplies and energy storage systems is considered as a promising candidate to solve the global energy dilemma. The photo-absorber and the energy storage material are integrated into the photocathode to effectively achieve a high-energy and high-efficiency energy system. In this work, we report the customized Janus-jointed photocathode design (integrating with highly efficient halide perovskite and tellurium composite electrode) and introduce it into the aqueous zinc-tellurium battery. The well-matched energy level of the Janus-jointed photocathode ensures the conversion of the photoenergy into electrical energy by transferring the photoexcited charge between each. As expected, in the photo-assisted recharging model, the decreased 0.1 V charge voltage and the extra 362 mA h g-1 at 100 mA g-1 demonstrated the significant merits of saving energy for such a photo-rechargeable Zn-Te (PRZT) battery. When the current density is 1000 mA g-1, the specific capacity of the prepared photocathode is 83% higher than that under dark conditions. More importantly, the photogenerated charge by the perovskite under light illumination could also directly photocharge the battery with no external current, indicating the self-powering traits. The rational design in this work is believed to provide a sustainable mode for efficient charging of the aqueous PRZT battery.

Genetically Programmable Vesicles for Enhancing CAR-T Therapy against Solid Tumors.

Chimeric antigen receptor-T (CAR-T) cell therapy has shown remarkable success in eradicating hematologic malignancies; however, its efficacy in treating solid tumors has always been limited due to the presence of an immune-suppressive tumor microenvironment (TME). Here, genetically programmable cellular vesicles expressing high-affinity anti-programmed death-ligand 1 single chain variable fragment (anti-PD-L1 scFv) loaded with glutamine antagonist (D@aPD-L1 NVs) are developed to metabolically dismantle the immunosuppressive TME and enhance the efficiency of anti-mesothelin CAR-T cells in orthotopic lung cancer. As anti-PD-L1 scFv can specifically bind to the programmed death-ligand 1 (PD-L1) on tumor cells, D@aPD-L1 NVs enable the targeted delivery of glutamine antagonists to the tumor site and address the upregulation of PD-L1 on tumor cells, which prevents the premature exhaustion of CAR-T cells. More importantly, D@aPD-L1 NVs effectively reduce the number of immunosuppressive cells and promote the recruitment of inflammatory cells and the secretion of inflammatory cytokines in tumor tissues. These unique features of D@aPD-L1 NVs improve the infiltration and effector functions of CAR-T cells, which ultimately enhance the anti-tumor ability and long-term memory immunity of CAR-T cells. The findings support that D@aPD-L1 NVs act as a promising drug to strengthen the effectiveness of CAR-T cells against solid tumors.

Achieving High Performance Electrode for Energy Storage with Advanced Prussian Blue-Drived Nanocomposites-A Review.

Recently, Prussian blue analogues (PBAs)-based anode materials (oxides, sulfides, selenides, phosphides, borides, and carbides) have been extensively investigated in the field of energy conversion and storage. This is due to PBAs' unique properties, including high theoretical specific capacity, environmental friendly, and low cost. We thoroughly discussed the formation of PBAs in conjunction with other materials. The performance of composite materials improves the electrochemical performance of its energy storage materials. Furthermore, new insights are provided for the manufacture of low-cost, high-capacity, and long-life battery materials in order to solve the difficulties in different electrode materials, combined with advanced manufacturing technology and principles. Finally, PBAs and their composites' future challenges and opportunities are discussed.

Vascular mimicry induced by m6A mediated IGFL2-AS1/AR axis contributes to pazopanib resistance in clear cell renal cell carcinoma.

Metastatic clear cell renal cell carcinoma (ccRCC) is a lethal sub-type of kidney cancer. Vascular mimicry (VM) has been postulated as an alternative route to supply tumors with nutrients, playing key role in tumor development. Whether VM development is linked to pazopanib efficacy, however, remains unclear. Here, our in vitro and in vivo models identified that VM development was profoundly increased in pazopanib resistant ccRCC as compared to the sensitive controls, which was due to the activation of IGFL2-AS1/AR/TWIST1 signaling. IGFL2-AS1, a m6A modified long coding RNA, was demethylated by METTL3/METTL14 complex and stabilized owing to its failing recognition by YTHDF2 upon chronic pazopanib treatment. Further mechanistic dissection illustrated that IGFL2-AS1 physically interacted with the 5'-UTR AR mRNA and neutralized the negative regulation of 5'-uORF (upstream open reading frame) on AR translation. Indeed, IGFL2-AS1 short of AR binding region failed to promote AR expression, VM formation and pazopanib resistance. In vivo xenografted mouse model also elucidated that inhibition of AR activity with enzalutamide or silence of IGFL2-AS1 with siRNAs all led to retarded growth of pazopanib resistant ccRCC tumors. Together, these results suggest that IGFL2-AS1 may represent a key player to mediate pazopanib-induced VM formation of ccRCC cells via regulating AR expression and targeting this newly identified IGFL2-AS1/AR signaling may help us to better suppress ccRCC VM formation and to increase the therapeutic efficacy of pazopanib.

HOOK1 Inhibits the Progression of Renal Cell Carcinoma via TGF-ß and TNFSF13B/VEGF-A Axis.

Accumulating evidence shows HOOK1 disordered in human malignancies. However, the clinicopathological and biological significance of HOOK1 in renal cell carcinoma (RCC) remains rarely studied. In this study, the authors demonstrate that HOOK1 is downregulated in RCC samples with predicted poorer clinical prognosis. Mechanistically, HOOK1 inhibits tumor growth and metastasis via canonical TGF-ß/ALK5/p-Smad3 and non-canonical TGF-ß/MEK/ERK/c-Myc pathway. At the same time, HOOK1 inhibits RCC angiogenesis and sunitinib resistance by promoting degradation of TNFSF13B through the ubiquitin-proteasome pathway. In addition, HOOK1 is transcriptionally regulated by nuclear factor E2F3 in VHL dependent manner. Notably, an agonist of HOOK1, meletin, is screened and it shows antitumor activity more effectively when combined with sunitinib or nivolumab than it is used alone. The findings reveal a pivotal role of HOOK1 in anti-cancer treatment, and identify a novel therapeutic strategy for renal cell carcinoma.