Search Medical Journals & Research Articles

Cell Contractile Force‐Mediated Morphogenetic Tissue Engineering via 4D Printed Degradable Hydrogel Scaffolds (Adv. Sci. 48/2025)

Self‐Powering 4D Bioprinting This cover illustrates a morphogenetic tissue regeneration process driven by an internal stimulus: cell contractile forces (CCFs). Generated through cytoskeletal interactions, CCFs are transmitted to the surrounding matrix and neighboring cells, exerting contractile forces on the printed constructs. Programming shape changes via CCFs provides a cytocompatible, self‐powering strategy for 4D bioprinting, eliminating the need for external stimulation. More details can be found in the Research Article by Eben Alsberg and co‐workers (DOI: 10.1002/advs.202507288). Self-Powering 4D Bioprinting This cover illustrates a morphogenetic tissue regeneration process driven by an internal stimulus: cell contractile forces (CCFs). Generated through cytoskeletal interactions, CCFs are transmitted to the surrounding matrix and neighboring cells, exerting contractile forces on the printed constructs. Programming shape changes via CCFs provides a cytocompatible, self-powering strategy for 4D bioprinting, eliminating the need for external stimulation. More details can be found in the Research Article by Eben Alsberg and co-workers (DOI: 10.1002/advs.202507288 ). Advanced Science, Volume 12, Issue 48, December 29, 2025.

CircPVT1 Promotes Lung Metastasis and Tumor Progression in Renal Cell Carcinoma by Encoding the cP104aa Peptide and Targeting EIF4A3 (Adv. Sci. 48/2025)

Renal Cell Carcinoma In renal cell carcinoma, the circular RNA circPVT1 can promote tumor progression by encoding a novel peptide, cP104aa. The Research Article by Ming Chen, Shuqiu Chen, Bin Xu, Weipu Mao, and co‐workers (DOI: 10.1002/advs.202501211) identifies that circPVT1 encodes a 104‐amino acid peptide, termed cP104aa. On the cover, the central circular structure represents circPVT1, with a green peptide segment extending from it, which corresponds to the cP104aa peptide. Renal Cell Carcinoma In renal cell carcinoma, the circular RNA circPVT1 can promote tumor progression by encoding a novel peptide, cP104aa. The Research Article by Ming Chen, Shuqiu Chen, Bin Xu, Weipu Mao, and co-workers (DOI: 10.1002/advs.202501211 ) identifies that circPVT1 encodes a 104-amino acid peptide, termed cP104aa. On the cover, the central circular structure represents circPVT1, with a green peptide segment extending from it, which corresponds to the cP104aa peptide. Advanced Science, Volume 12, Issue 48, December 29, 2025.

Pathogenicity of Mediator Complex Subunit 27 (MED27) in a Neurodevelopmental Disorder with Cerebellar Atrophy (Adv. Sci. 48/2025)

Neurodevelopmental Disorder This cover features a comprehensive study on the pathogenic mechanisms underlying a neurodevelopmental disorder caused by deleterious variants in the MED27 gene. MED27 is a key subunit of the human Mediator complex (MED). Pathogenic genetic variants in MED27 destabilize MED, leading to its impaired DNA occupancy, disrupted chromatin interactions, and transcriptional dysregulation of critical downstream genes essential for early neurogenesis and cerebellar development. More details can be found in the Research Article by Nuermila Yiliyaer, Xiaocheng Li, Tianyu Guo, Shen Gu and co‐workers (DOI: 10.1002/advs.202505535). Neurodevelopmental Disorder This cover features a comprehensive study on the pathogenic mechanisms underlying a neurodevelopmental disorder caused by deleterious variants in the MED27 gene. MED27 is a key subunit of the human Mediator complex (MED). Pathogenic genetic variants in MED27 destabilize MED, leading to its impaired DNA occupancy, disrupted chromatin interactions, and transcriptional dysregulation of critical downstream genes essential for early neurogenesis and cerebellar development. More details can be found in the Research Article by Nuermila Yiliyaer, Xiaocheng Li, Tianyu Guo, Shen Gu and co-workers (DOI: 10.1002/advs.202505535 ). Advanced Science, Volume 12, Issue 48, December 29, 2025.

Osmotically Tunable Microdroplets Enable Amplification‐Free CRISPR Detection of Gene Doping (Adv. Sci. 48/2025)

Amplification‐Free Detections This illustration connects gene doping to an innovative diagnostic solution. A microfluidic device generates osmotically tunable double emulsion droplets that serve as isolated picoliter reactors. Inside, the sample is mixed with a CRISPR‐Cas system for amplification‐free, highly sensitive detection. Enhanced signals visually confirm detection, demonstrating a simple, powerful, and rapid diagnostic platform. More details can be found in the Research Article by Changmin Sung, Chang‐Soo Lee, and co‐workers (DOI: 10.1002/advs.202515861). Amplification-Free Detections This illustration connects gene doping to an innovative diagnostic solution. A microfluidic device generates osmotically tunable double emulsion droplets that serve as isolated picoliter reactors. Inside, the sample is mixed with a CRISPR-Cas system for amplification-free, highly sensitive detection. Enhanced signals visually confirm detection, demonstrating a simple, powerful, and rapid diagnostic platform. More details can be found in the Research Article by Changmin Sung, Chang-Soo Lee, and co-workers (DOI: 10.1002/advs.202515861 ). Advanced Science, Volume 12, Issue 48, December 29, 2025.

4D Insights into Coral Biomineralization: Effects of Ocean Acidification on the Early Skeleton Development of a Stony Coral (Adv. Sci. 48/2025)

Coral Skeleton Growth Stony coral skeletons form through two main growth zones, rapid accretion deposits (RADs) and thickening deposits (TDs), that emerge in the earliest life stages. Ocean acidification alters their growth, increasing TD density via a shift toward more crystalline calcium carbonate phases, and reducing RADs development. The result is a denser yet structurally weaker skeleton, redefining coral resilience under future ocean scenarios. More detiails can be found in the Research Article by Federica Scucchia, Paul Zaslansky, and co‐workers (DOI: 10.1002/advs.202508585). Coral Skeleton Growth Stony coral skeletons form through two main growth zones, rapid accretion deposits (RADs) and thickening deposits (TDs), that emerge in the earliest life stages. Ocean acidification alters their growth, increasing TD density via a shift toward more crystalline calcium carbonate phases, and reducing RADs development. The result is a denser yet structurally weaker skeleton, redefining coral resilience under future ocean scenarios. More detiails can be found in the Research Article by Federica Scucchia, Paul Zaslansky, and co-workers (DOI: 10.1002/advs.202508585 ). Advanced Science, Volume 12, Issue 48, December 29, 2025.

Hot‐Pressing Annealing‐Induced Light Utilization Enhancement and Crystallinity Optimization Enable High‐Performance Narrowband Ultraviolet Photodetectors for Real‐Time Ultraviolet Radiation Monitors

By utilizing a hot‐pressing (HP) annealing strategy, Cs3Cu2I5 films with larger grains vertically spanning the entire thickness are fabricated. Because HP annealing enhances light utilization and charge transport in Cs3Cu2I5/GaN heterojunction, the HP device achieves superior detection performance while maintaining narrowband photoresponse to UVA/UVB lights (280–375 nm). Finally, the HP device is successfully applied in real‐time UV radiation monitors. Abstract The real‐time ultraviolet (UV) radiation monitor can protect personal healthcare by real‐time monitoring UV radiation, highlighting the urgent need for high‐performance self‐powered narrowband UV detectors that can selectively response to UVA and UVB wavelengths. Existing narrowband photodetectors often rely on a surface defect‐assisted charge collection narrowing strategy, which inevitably compromises device performance. In this study, a hot‐pressing (HP) annealing strategy is introduced to prepare high‐quality Cs3Cu2I5 films with large grains vertically spanning the entire thickness. The HP annealing reduces the defect density and light loss in the 280−375 nm range in the Cs3Cu2I5 films, and enhances the charge transport and collection in the Cs3Cu2I5/GaN heterojunction. As a result, the Cs3Cu2I5/GaN‐based photodetectors achieve self‐powered UV detection performance with low dark current (1.50 × 10−12 A), large responsivity (0.22 A W−1), high detectivity (6.40 × 1011 Jones), and fast response speed (26/117 µs), while maintaining narrowband detection capabilities (280−375 nm). Furthermore, the devices implement a real‐time and continuous UV radiation monitor to help prevent diseases caused by excessive UV radiation. This work not only propels the evolution of high‐performance narrowband UV photodetectors but also links technological innovation with equipment designed for practical applications. By utilizing a hot-pressing (HP) annealing strategy, Cs 3 Cu 2 I 5 films with larger grains vertically spanning the entire thickness are fabricated. Because HP annealing enhances light utilization and charge transport in Cs 3 Cu 2 I 5 /GaN heterojunction, the HP device achieves superior detection performance while maintaining narrowband photoresponse to UVA/UVB lights (280–375 nm). Finally, the HP device is successfully applied in real-time UV radiation monitors. Abstract The real-time ultraviolet (UV) radiation monitor can protect personal healthcare by real-time monitoring UV radiation, highlighting the urgent need for high-performance self-powered narrowband UV detectors that can selectively response to UVA and UVB wavelengths. Existing narrowband photodetectors often rely on a surface defect-assisted charge collection narrowing strategy, which inevitably compromises device performance. In this study, a hot-pressing (HP) annealing strategy is introduced to prepare high-quality Cs 3 Cu 2 I 5 films with large grains vertically spanning the entire thickness. The HP annealing reduces the defect density and light loss in the 280−375 nm range in the Cs 3 Cu 2 I 5 films, and enhances the charge transport and collection in the Cs 3 Cu 2 I 5 /GaN heterojunction. As a result, the Cs 3 Cu 2 I 5 /GaN-based photodetectors achieve self-powered UV detection performance with low dark current (1.50 × 10 −12 A), large responsivity (0.22 A W −1 ), high detectivity (6.40 × 10 11 Jones), and fast response speed (26/117 µs), while maintaining narrowband detection capabilities (280−375 nm). Furthermore, the devices implement a real-time and continuous UV radiation monitor to help prevent diseases caused by excessive UV radiation. This work not only propels the evolution of high-performance narrowband UV photodetectors but also links technological innovation with equipment designed for practical applications. Advanced Science, Volume 12, Issue 48, December 29, 2025.

MUC15 Ectodomain Architecture Regulates Integrin Clustering to Control Cancer Metastasis

This study uncovers a size‐dependent adhesion paradigm, demonstrating that the glycocalyx protein MUC15 suppresses pancreatic cancer progression by attenuating integrin activation, focal adhesion assembly, and YAP mechanotransduction. Integrating computational modeling and experimental validation, the work reveals a mechanical mechanism by which MUC15 constrains metastatic behavior, offering new insights into glycocalyx‐mediated cancer regulation. Abstract Cancer metastasis is governed by physical cues at the cell‐matrix interface, with matrix stiffness, ligand density, and topography established as key determinants. Here, a fourth critical factor in cancer metastasis, the architecture of the cell‐surface glycocalyx is identified. Using MUC15 as a representative small glycoprotein, mathematical modeling and domain truncation experiments are combined to show that glycoprotein size distribution governs integrin adhesion states and metastatic outcomes. MUC15 localizes to focal adhesions and interact with integrins, while larger glycoproteins such as MUC1 are sterically excluded. These physical effects, rather than intracellular signaling, dictate adhesion state transitions: removing MUC15's ectodomain eliminated its anti‐metastatic effects, whereas removal of its cytoplasmic tail has no effect. In in vivo pancreatic cancer models, modulating MUC15 levels controlled metastasis as predicted by the mathematical model. These findings establish glycocalyx architecture as a mechanical regulator of cancer progression and suggest therapeutic strategies targeting glycoprotein size distribution. This study uncovers a size-dependent adhesion paradigm, demonstrating that the glycocalyx protein MUC15 suppresses pancreatic cancer progression by attenuating integrin activation, focal adhesion assembly, and YAP mechanotransduction. Integrating computational modeling and experimental validation, the work reveals a mechanical mechanism by which MUC15 constrains metastatic behavior, offering new insights into glycocalyx-mediated cancer regulation. Abstract Cancer metastasis is governed by physical cues at the cell-matrix interface, with matrix stiffness, ligand density, and topography established as key determinants. Here, a fourth critical factor in cancer metastasis, the architecture of the cell-surface glycocalyx is identified. Using MUC15 as a representative small glycoprotein, mathematical modeling and domain truncation experiments are combined to show that glycoprotein size distribution governs integrin adhesion states and metastatic outcomes. MUC15 localizes to focal adhesions and interact with integrins, while larger glycoproteins such as MUC1 are sterically excluded. These physical effects, rather than intracellular signaling, dictate adhesion state transitions: removing MUC15's ectodomain eliminated its anti-metastatic effects, whereas removal of its cytoplasmic tail has no effect. In in vivo pancreatic cancer models, modulating MUC15 levels controlled metastasis as predicted by the mathematical model. These findings establish glycocalyx architecture as a mechanical regulator of cancer progression and suggest therapeutic strategies targeting glycoprotein size distribution. Advanced Science, Volume 12, Issue 48, December 29, 2025.

Interconversions between RNS Revealed by Transient Voltammetry with Porphyrin‐Modified Carbon Nanopipettes in Single Living Cells

By using porphyrin modified conductive nanopipettes, transient voltammetry can be directly applied to reveal the dynamic and complex electrochemical reactions between the reactive nitrogen species inside the single living cells. Abstract Reactive nitrogen species (RNS) play crucial roles in cellular signaling, but their quantification is very challenging due to low‐abundant nature and complex conversions with other reactive molecules in the cells. The well‐established amperometry methods have been widely used to measure the RNS inside the living cells, while the nanometer‐sized tip is limited by the steady‐state studies. In this paper, conductive nanopipettes (CNPs) with porphyrin complexes are functionalized, which allow direct transient voltammetry tests to differentiate and quantify the RNS based on the peak potential and current. It is shown that the oxidation of NO2‒ can produce a nitrogen dioxide (NO2) intermediate, and a CEC (chemical‐electrochemical‐chemical) mechanism is proposed. Moreover, this platform with transient voltammetry enables real‐time quantification of cellular RNS and reveals the dynamic interconversions within RNS, providing valuable insights into their roles in cellular processes. By using porphyrin modified conductive nanopipettes, transient voltammetry can be directly applied to reveal the dynamic and complex electrochemical reactions between the reactive nitrogen species inside the single living cells. Abstract Reactive nitrogen species (RNS) play crucial roles in cellular signaling, but their quantification is very challenging due to low-abundant nature and complex conversions with other reactive molecules in the cells. The well-established amperometry methods have been widely used to measure the RNS inside the living cells, while the nanometer-sized tip is limited by the steady-state studies. In this paper, conductive nanopipettes (CNPs) with porphyrin complexes are functionalized, which allow direct transient voltammetry tests to differentiate and quantify the RNS based on the peak potential and current. It is shown that the oxidation of NO 2 ‒ can produce a nitrogen dioxide (NO 2 ) intermediate, and a CEC (chemical-electrochemical-chemical) mechanism is proposed. Moreover, this platform with transient voltammetry enables real-time quantification of cellular RNS and reveals the dynamic interconversions within RNS, providing valuable insights into their roles in cellular processes. Advanced Science, Volume 12, Issue 48, December 29, 2025.

A Robust Synthesis of Fluorosurfactants with Tunable Functionalities via a Two‐Step Reaction

The fluorosurfactants are synthesized through a two‐step reaction, and demonstrated excellent performance in droplet microfluidics. In addition, they exhibited tunable functionalities at the droplet interface via hydrogen bonding and coordination interactions. Abstract Fluorosurfactant‐stabilized microdroplets hold significant promise for a wide range of applications, owing to their biological and chemical inertness. However, conventional synthetic routes for fluorosurfactants typically require multiple reaction steps and stringent conditions, such as high temperatures and anaerobic environments. This complexity poses a significant limitation to the development of fluorosurfactant synthesis and its subsequent applications in droplet‐based systems. In this work, a robust two‐step synthesis of fluorosurfactants with tunable functionalities is presented. Microdroplets stabilized by these fluorosurfactants exhibit enhanced stability and biocompatibility. Notably, these fluorosurfactants facilitate the formation of nanodroplets that efficiently transport and concentrate fluorophores with high selectivity. Furthermore, it is demonstrated that colloidal self‐assemblies with distinct structures can be engineered by modulating interactions between the fluorosurfactants and colloidal particles. The synthetic approach provides a strategy for the rapid production of functional fluorosurfactants under mild conditions, enabling droplet‐based microfluidic techniques with applications in biology and material science. The fluorosurfactants are synthesized through a two-step reaction, and demonstrated excellent performance in droplet microfluidics. In addition, they exhibited tunable functionalities at the droplet interface via hydrogen bonding and coordination interactions. Abstract Fluorosurfactant-stabilized microdroplets hold significant promise for a wide range of applications, owing to their biological and chemical inertness. However, conventional synthetic routes for fluorosurfactants typically require multiple reaction steps and stringent conditions, such as high temperatures and anaerobic environments. This complexity poses a significant limitation to the development of fluorosurfactant synthesis and its subsequent applications in droplet-based systems. In this work, a robust two-step synthesis of fluorosurfactants with tunable functionalities is presented. Microdroplets stabilized by these fluorosurfactants exhibit enhanced stability and biocompatibility. Notably, these fluorosurfactants facilitate the formation of nanodroplets that efficiently transport and concentrate fluorophores with high selectivity. Furthermore, it is demonstrated that colloidal self-assemblies with distinct structures can be engineered by modulating interactions between the fluorosurfactants and colloidal particles. The synthetic approach provides a strategy for the rapid production of functional fluorosurfactants under mild conditions, enabling droplet-based microfluidic techniques with applications in biology and material science. Advanced Science, Volume 12, Issue 48, December 29, 2025.

Aloe‐Emodin Targeting FOXC2 Disrupts NETs Formation and EMT‐Driven Postoperative Peritoneal Adhesion Through TGF‐β1‐Smad2/3 Pathway

Forkhead box protein C2 (FOXC2) is highlighted as a pivotal effector in postoperative peritoneal adhesion (PPA) formation. Mechanically, FOXC2 mediates NETs‐induced EMT alterations through the TGF‐β1‐Smad2/3 pathway. Aloe‐emodin (AE) ameliorates FOXC2‐driven fibrosis by blocking NETs formation and EMT changes through this pathway. AE binds FOXC2 at Ser125, establishing FOXC2 as a therapeutic target and demonstrating AE's potential in attenuating PPA. Abstract Postoperative peritoneal adhesion (PPA) develops through TGF‐β1‐driven fibrotic remodeling, characterized by neutrophil extracellular trap (NETs)‐induced aberrant epithelial‐to‐mesenchymal transition (EMT) deposition. Although aloe‐emodin (AE) exhibits anti‐fibrosis potential, its molecular mechanisms remain elusive. Forkhead box protein C2 (FOXC2) is a critical regulator of fibrotic tissue formation, yet its role in PPA is unknown. Here, it is demonstrated that FOXC2 expression is elevated in human ileostomy tissue, PPA rodent model, and TGF‐β1‐exposed peritoneal mesothelial cells (PMCs), where it orchestrates NETs formation and extracellular matrix (ECM) remodeling. Mechanically, CRISPR/Cas‐based knockdown and overexpression of FOXC2 alter EMT changes in PMCs, which is achieved via TGF‐β1‐Smad2/3 signaling. FOXC2 functions as a dual mediator and amplifier through the TGF‐β1‐Smad2/3 pathway feedback loop to drive EMT alterations. Its overexpression further induces neutrophil recruitment and NETs formation, exacerbating EMT in PMCs. Notably, AE ameliorates FOXC2‐driven peritoneal fibrosis by impeding NETs formation and EMT changes through the TGF‐β1‐Smad2/3 pathway. Moreover, AE binds directly to FOXC2, and the Ser125 residue is critical for the binding of FOXC2 to AE. These findings identify FOXC2 as a pivotal effector in fibrotic responses during PPA formation and reveal that AE targeting the Ser125 residue of FOXC2 may be a promising therapeutic approach to attenuate PPA. Forkhead box protein C2 (FOXC2) is highlighted as a pivotal effector in postoperative peritoneal adhesion (PPA) formation. Mechanically, FOXC2 mediates NETs-induced EMT alterations through the TGF-β1-Smad2/3 pathway. Aloe-emodin (AE) ameliorates FOXC2-driven fibrosis by blocking NETs formation and EMT changes through this pathway. AE binds FOXC2 at Ser125, establishing FOXC2 as a therapeutic target and demonstrating AE's potential in attenuating PPA. Abstract Postoperative peritoneal adhesion (PPA) develops through TGF-β1-driven fibrotic remodeling, characterized by neutrophil extracellular trap (NETs)-induced aberrant epithelial-to-mesenchymal transition (EMT) deposition. Although aloe-emodin (AE) exhibits anti-fibrosis potential, its molecular mechanisms remain elusive. Forkhead box protein C2 (FOXC2) is a critical regulator of fibrotic tissue formation, yet its role in PPA is unknown. Here, it is demonstrated that FOXC2 expression is elevated in human ileostomy tissue, PPA rodent model, and TGF-β1-exposed peritoneal mesothelial cells (PMCs), where it orchestrates NETs formation and extracellular matrix (ECM) remodeling. Mechanically, CRISPR/Cas-based knockdown and overexpression of FOXC2 alter EMT changes in PMCs, which is achieved via TGF-β1-Smad2/3 signaling. FOXC2 functions as a dual mediator and amplifier through the TGF-β1-Smad2/3 pathway feedback loop to drive EMT alterations. Its overexpression further induces neutrophil recruitment and NETs formation, exacerbating EMT in PMCs. Notably, AE ameliorates FOXC2-driven peritoneal fibrosis by impeding NETs formation and EMT changes through the TGF-β1-Smad2/3 pathway. Moreover, AE binds directly to FOXC2, and the Ser125 residue is critical for the binding of FOXC2 to AE. These findings identify FOXC2 as a pivotal effector in fibrotic responses during PPA formation and reveal that AE targeting the Ser125 residue of FOXC2 may be a promising therapeutic approach to attenuate PPA. Advanced Science, Volume 12, Issue 48, December 29, 2025.

SIP‐SRS Imaging of Cell Wall Synthesis Identifies a Synergy between Micafungin and Amphotericin B

We employed glucose‐d7–based stable isotope probe‐assisted SRS microscopy (SIP‐SRS) C–D imaging to visualize fungal cell wall synthesis and remodeling under antifungal treatment. Amphotericin B (AmB) induced notable daughter cell wall thickening, prompting a combinational therapy with AmB and micafungin. This approach synergistically inhibited fungal growth, revealing therapeutic potential through targeted cell wall remodeling analysis. Abstract Candida species causes life‐threatening infections in immunocompromised individuals and presents a formidable challenge in clinical practice. This challenge is exacerbated by the growing prevalence of drug resistance, particularly against the last resort antifungals such as amphotericin B (AmB). The fungal cell wall, known for its dynamic reorganization in response to growth demands and host threats, are recognized as a key drug target. In this study, stable isotope probe‐assisted SRS microscopy (SIP‐SRS) is harnessed to directly visualize and interrogate the dynamics of fungal cell wall synthesis under various antifungal treatments. A striking observation is the thickening of the cell wall in newly synthesized daughter cells under AmB treatment. Based on this finding, a synergistic inhibition of fungal growth is demonstrated by AmB and micafungin, an antifungal agent targeting cell wall synthesis. These results not only advance the understanding of fungal physiology at the molecular level but also open promising avenues for combating drug‐resistant fungal infections. We employed glucose-d7–based stable isotope probe-assisted SRS microscopy (SIP-SRS) C–D imaging to visualize fungal cell wall synthesis and remodeling under antifungal treatment. Amphotericin B (AmB) induced notable daughter cell wall thickening, prompting a combinational therapy with AmB and micafungin. This approach synergistically inhibited fungal growth, revealing therapeutic potential through targeted cell wall remodeling analysis. Abstract Candida species causes life-threatening infections in immunocompromised individuals and presents a formidable challenge in clinical practice. This challenge is exacerbated by the growing prevalence of drug resistance, particularly against the last resort antifungals such as amphotericin B (AmB). The fungal cell wall, known for its dynamic reorganization in response to growth demands and host threats, are recognized as a key drug target. In this study, stable isotope probe-assisted SRS microscopy (SIP-SRS) is harnessed to directly visualize and interrogate the dynamics of fungal cell wall synthesis under various antifungal treatments. A striking observation is the thickening of the cell wall in newly synthesized daughter cells under AmB treatment. Based on this finding, a synergistic inhibition of fungal growth is demonstrated by AmB and micafungin, an antifungal agent targeting cell wall synthesis. These results not only advance the understanding of fungal physiology at the molecular level but also open promising avenues for combating drug-resistant fungal infections. Advanced Science, Volume 12, Issue 48, December 29, 2025.

METTL10‐Mediated PIAS3 Methylation Links Purine Metabolism to Gastric Cancer Progression

METTL10‐mediated methylation of PIAS3 at K442 inhibits its SUMO E3 ligase activity toward MITF. This reduces MITF SUMOylation and subsequent RNF4‐mediated ubiquitination, leading to MITF protein accumulation and gastric cancer progression. Abstract Metabolic dysregulation plays a significant role in the development of gastric cancer (GC). However, the mechanisms that control this change and its impact on GC progression remain poorly understood. In this study, it is demonstrated that methyltransferase‐like 10 (METTL10) is a key regulator of gastric tumor formation by enhancing purine metabolism in GC cells. It is discovered that METTL10 methylates the protein inhibitor of activated STAT3 (PIAS3) at the lysine 442 (K442) residue, which interferes with the interaction of PIAS3 with microphthalmia‐associated transcription factor (MITF). As a result, the sumoylation and ubiquitination of MITF by PIAS3 are reduced, leading to MITF stabilization and activation of purine metabolism. Importantly, both the accumulation of MITF and the methylation of K442 in PIAS3 are required for the oncogenic effects of METTL10, and both factors are closely linked to poor clinical outcomes in GC. Furthermore, this study identified a compound, LZQ‐02‐023‐01, which effectively induces the METTL10‐mediated ubiquitination and degradation of MITF, thereby reducing the oncogenic activity of METTL10. The findings suggest that METTL10 plays an important role in reprogramming purine metabolism, which promotes GC, highlighting it as a potential therapeutic target for GC treatment. METTL10-mediated methylation of PIAS3 at K442 inhibits its SUMO E3 ligase activity toward MITF. This reduces MITF SUMOylation and subsequent RNF4-mediated ubiquitination, leading to MITF protein accumulation and gastric cancer progression. Abstract Metabolic dysregulation plays a significant role in the development of gastric cancer (GC). However, the mechanisms that control this change and its impact on GC progression remain poorly understood. In this study, it is demonstrated that methyltransferase-like 10 (METTL10) is a key regulator of gastric tumor formation by enhancing purine metabolism in GC cells. It is discovered that METTL10 methylates the protein inhibitor of activated STAT3 (PIAS3) at the lysine 442 (K442) residue, which interferes with the interaction of PIAS3 with microphthalmia-associated transcription factor (MITF). As a result, the sumoylation and ubiquitination of MITF by PIAS3 are reduced, leading to MITF stabilization and activation of purine metabolism. Importantly, both the accumulation of MITF and the methylation of K442 in PIAS3 are required for the oncogenic effects of METTL10, and both factors are closely linked to poor clinical outcomes in GC. Furthermore, this study identified a compound, LZQ-02-023-01, which effectively induces the METTL10-mediated ubiquitination and degradation of MITF, thereby reducing the oncogenic activity of METTL10. The findings suggest that METTL10 plays an important role in reprogramming purine metabolism, which promotes GC, highlighting it as a potential therapeutic target for GC treatment. Advanced Science, Volume 12, Issue 48, December 29, 2025.

CircSMEK1 Suppresses HCC via the hnRNPK‐IGF2‐AKT Axis: A Diagnostic Biomarker and Therapeutic Target

CircSMEK1 is downregulated in MASH/HCC and predicts poor prognosis. It suppresses tumor progression by promoting hnRNPK ubiquitination and inhibiting the IGF2/PI3K/AKT axis, while its loss activates immunosuppressive cancer‐associated fibroblasts. Serum circSMEK1 serves as a non‐invasive diagnostic biomarker, and its restoration potently inhibits HCC growth and metastasis in vivo. Abstract The mechanism underlying metabolic dysfunction‐associated steatohepatitis (MASH) to hepatocellular carcinoma (HCC) is elusive, and whether circRNA can serve as biomarker or therapeutic target for MASH/HCC needs to be systematically explored. Integrative transcriptomic analysis of circRNA from MASH and HCC were performed. Multi‐cohort analyses of serum and tissues from MASH and HCC patients (n = 206) were conducted. Mechanisms are explored via RNA‐protein interaction assays, CRISPR‐mediated knockdown, and xenograft/PiggyBac‐mediated mice models. circSMEK1 is significantly decreased in MASH/HCC tissues and serum, correlating with tumor size, vascular invasion, and overall survival. Mechanistically, nuclear circSMEK1 binds hnRNPK, promoting its ubiquitin‐mediated degradation, suppressing IGF2 transcription and PI3K/AKT signaling. Loss of circSMEK1 elevated autocrine IGF2 in HCC promoting tumor growth, also activated AKT in cancer‐associated fibroblasts through paracrine, fostering an immunosuppressive microenvironment. SF3B4 overexpression drove circSMEK1 depletion in HCC. In murine models, circSMEK1 restoration inhibited tumor growth and metastasis. circSMEK1 is a tumor‐suppressor in MASH/HCC through the hnRNPK‐IGF2‐AKT axis. The serum level of circSMEK1 has non‐invasive diagnostic value for HCC (AUC = 0.790), as well as potential diagnostic utility for early HCC or high‐risk MASH, owing to its key role in bridging MASH to HCC progression. Restoring of circSMEK1, alone or combined with IGF2 inhibitors, proposing a novel therapeutic strategy for HCC. CircSMEK1 is downregulated in MASH/HCC and predicts poor prognosis. It suppresses tumor progression by promoting hnRNPK ubiquitination and inhibiting the IGF2/PI3K/AKT axis, while its loss activates immunosuppressive cancer-associated fibroblasts. Serum circSMEK1 serves as a non-invasive diagnostic biomarker, and its restoration potently inhibits HCC growth and metastasis in vivo. Abstract The mechanism underlying metabolic dysfunction-associated steatohepatitis (MASH) to hepatocellular carcinoma (HCC) is elusive, and whether circRNA can serve as biomarker or therapeutic target for MASH/HCC needs to be systematically explored. Integrative transcriptomic analysis of circRNA from MASH and HCC were performed. Multi-cohort analyses of serum and tissues from MASH and HCC patients ( n = 206) were conducted. Mechanisms are explored via RNA-protein interaction assays, CRISPR-mediated knockdown, and xenograft/PiggyBac-mediated mice models. circSMEK1 is significantly decreased in MASH/HCC tissues and serum, correlating with tumor size, vascular invasion, and overall survival. Mechanistically, nuclear circSMEK1 binds hnRNPK, promoting its ubiquitin-mediated degradation, suppressing IGF2 transcription and PI3K/AKT signaling. Loss of circSMEK1 elevated autocrine IGF2 in HCC promoting tumor growth, also activated AKT in cancer-associated fibroblasts through paracrine, fostering an immunosuppressive microenvironment. SF3B4 overexpression drove circSMEK1 depletion in HCC. In murine models, circSMEK1 restoration inhibited tumor growth and metastasis. circSMEK1 is a tumor-suppressor in MASH/HCC through the hnRNPK-IGF2-AKT axis. The serum level of circSMEK1 has non-invasive diagnostic value for HCC (AUC = 0.790), as well as potential diagnostic utility for early HCC or high-risk MASH, owing to its key role in bridging MASH to HCC progression. Restoring of circSMEK1, alone or combined with IGF2 inhibitors, proposing a novel therapeutic strategy for HCC. Advanced Science, Volume 12, Issue 48, December 29, 2025.

Integrin α8‐Mediated Pericyte Morphogenesis Controls Blood‐Brain Barrier Integrity

This study highlights that ITGA8 impacts pericyte morphology and function, both crucial for BBB integrity, via RhoA/ROCK signaling, thus influencing TGF‐β1 activation through cytoskeletal tension and ECM interactions. Notably, in post‐ischemic recovery models, ITGA8 deficiency exacerbates vascular dysfunction by impairing pericyte‐mediated BBB reconstruction, whereas therapeutic ITGA8 overexpression enhances vascular stabilization and recovery. Abstract Pericytes exhibits distinct morphological features on microvessels during various stages of brain‐blood barrier (BBB) development and neurological disorders. However, the underlying mechanisms by which pericyte morphology influences BBB integrity are not yet fully understood. Integrin α8 (ITGA8) is prominently expressed in mature pericytes, which tightly associate with endothelial cells during BBB maturation and post‐ischemic vascular remodeling. ITGA8‐deficient mice shows the disrupted pericyte morphology, including shortened processes and reduced vascular coverage, leads to compromised BBB integrity. Mechanistically, ITGA8 regulates pericyte morphology via the Rho‐ROCK signaling, subsequently impacting BBB function through TGF‐β1 activation, which underscores its role in cytoskeletal organization and microvascular stability. In an ischemic stroke model, ITGA8 deficiency results in increased BBB permeability, reduced pericyte coverage, and worsened neurological recovery. Conversely, adeno‐associated virus (AAV)‐mediated ITGA8 overexpression restores pericyte morphology and improveS post‐stroke neurological outcomes. ITGA8 is identified as a key regulator of pericyte morphology and function, which are essential for maintaining BBB integrity, thereby highlighting the therapeutic potential of targeting ITGA8 for BBB repair and neurovascular recovery. This study highlights that ITGA8 impacts pericyte morphology and function, both crucial for BBB integrity, via RhoA/ROCK signaling, thus influencing TGF-β1 activation through cytoskeletal tension and ECM interactions. Notably, in post-ischemic recovery models, ITGA8 deficiency exacerbates vascular dysfunction by impairing pericyte-mediated BBB reconstruction, whereas therapeutic ITGA8 overexpression enhances vascular stabilization and recovery. Abstract Pericytes exhibits distinct morphological features on microvessels during various stages of brain-blood barrier (BBB) development and neurological disorders. However, the underlying mechanisms by which pericyte morphology influences BBB integrity are not yet fully understood. Integrin α8 ( ITGA8 ) is prominently expressed in mature pericytes, which tightly associate with endothelial cells during BBB maturation and post-ischemic vascular remodeling. ITGA8 -deficient mice shows the disrupted pericyte morphology, including shortened processes and reduced vascular coverage, leads to compromised BBB integrity. Mechanistically, ITGA8 regulates pericyte morphology via the Rho-ROCK signaling, subsequently impacting BBB function through TGF-β1 activation, which underscores its role in cytoskeletal organization and microvascular stability. In an ischemic stroke model, ITGA8 deficiency results in increased BBB permeability, reduced pericyte coverage, and worsened neurological recovery. Conversely, adeno-associated virus (AAV)-mediated ITGA8 overexpression restores pericyte morphology and improveS post-stroke neurological outcomes. ITGA8 is identified as a key regulator of pericyte morphology and function, which are essential for maintaining BBB integrity, thereby highlighting the therapeutic potential of targeting ITGA8 for BBB repair and neurovascular recovery. Advanced Science, Volume 12, Issue 48, December 29, 2025.

Supercontinuum Generation in Soft Glass Photonic Crystal Fibers Developed Based on 3D Printed Preforms

This research investigates whether modern 3D glass printing can be used to develop advanced photonic crystal fibers suitable for supercontinuum generation. The team designs and fabricates a lead‐borate glass fiber with high nonlinearity, achieving an octave‐spanning spectrum in the mid‐infrared range. 3D glass printing represents a promising alternative to the conventional fabrication of complex optical fibers using the stack‐and‐draw method, which requires manual preform assembly. Abstract The readiness level of 3D glass printing technology for optical fiber development is explored. A preform of an air‐glass photonic crystal fiber is printed with synthesized in‐house lead borate glass using a custom‐made 3D printer. The fiber is single‐moded at a wavelength of 1.5 µm and has flat anomalous dispersion in the infrared range above 1.5 µm with a zero‐dispersion wavelength at 1.7 µm. An octave spanning supercontinuum from 1.1 to 2.2 µm is obtained by pumping the 22 cm long section of the printed fiber in the anomalous dispersion regime with 100 fs pulses at 1560 nm wavelength using a standard off‐the‐shelf fiber femtosecond laser. Despite internal structural defects, the results indicate that early‐stage 3D glass printing can enable the development of preforms for nonlinear fibers dedicated to supercontinuum generation with spectral widths comparable to state‐of‐the‐art manually assembled PCFs, but still with considerably higher losses. This research investigates whether modern 3D glass printing can be used to develop advanced photonic crystal fibers suitable for supercontinuum generation. The team designs and fabricates a lead-borate glass fiber with high nonlinearity, achieving an octave-spanning spectrum in the mid-infrared range. 3D glass printing represents a promising alternative to the conventional fabrication of complex optical fibers using the stack-and-draw method, which requires manual preform assembly. Abstract The readiness level of 3D glass printing technology for optical fiber development is explored. A preform of an air-glass photonic crystal fiber is printed with synthesized in-house lead borate glass using a custom-made 3D printer. The fiber is single-moded at a wavelength of 1.5 µm and has flat anomalous dispersion in the infrared range above 1.5 µm with a zero-dispersion wavelength at 1.7 µm. An octave spanning supercontinuum from 1.1 to 2.2 µm is obtained by pumping the 22 cm long section of the printed fiber in the anomalous dispersion regime with 100 fs pulses at 1560 nm wavelength using a standard off-the-shelf fiber femtosecond laser. Despite internal structural defects, the results indicate that early-stage 3D glass printing can enable the development of preforms for nonlinear fibers dedicated to supercontinuum generation with spectral widths comparable to state-of-the-art manually assembled PCFs, but still with considerably higher losses. Advanced Science, Volume 12, Issue 48, December 29, 2025.