This issue features 10 cutting-edge research achievements covering popular areas such as placental development, heart failure, colorectal cancer, cognitive neural mechanisms, tumor immunology, lung adenocarcinoma, Parkinson’s disease, anti-infective immunity, depression, liver cancer, and more. Among them, the Cang Yong team from ShanghaiTech University reported in Nature on a novel HuR molecular gel degrader, providing a breakthrough therapy for BRAF-mutated colorectal cancer; Liu Jun’s team from Ruijin Hospital at Shanghai Jiao Tong University published positive clinical data for Phase I gene therapy for Parkinson’s disease in Nature Medicine; The team from Huazhong University of Science and Technology discovered the mitochondrial switch PARK7, which reverses T cell exhaustion. Providing cutting-edge references for disease mechanism research, new drug development, and intellectual property layout.

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1. TMEM63B regulates nucleoplasm transport to drive placental development

On June 8, Zhang Yang’s team at Shenzhen Bay Laboratory, together with Cao Bin’s team from Xiamen University, published original research in Nature Communications, elucidating for the first time the core mechanism by which transmembrane mechanosensing TMEM63B molecules drive normal placental development by regulating nucleoplasm transport pathways. This fills a long-standing research gap in the field of mechanical microenvironment signal regulation of perinatal placental homeostasis.
As the core functional organ that sustains fetal growth in utero, the placenta’s development highly depends on the precise sequential regulation of trophoblast cell proliferation and differentiation. High-risk pregnancy complications such as preeclampsia, unexplained recurrent miscarriage, and fetal growth restriction are mostly directly linked to trophoblast cell cycle disorders, but the field has long failed to clearly understand how mechanical sensing signals link key nodes in the nuclear cycle regulatory network. Previously TMEM63B was only labeled by functional genomics as membrane proteins potentially involved in mitotic mechanics regulation and as perinatal death candidate genes, with their physiological functions completely unknown.
This study confirms that TMEM63B can directly bind to and stabilize the core transport components of the nuclear pore complex, mediating nucleoplasmic shuttles in response to the cyclic repressor CDKN1A/p21 response to osmotic pressure and matrix stiffness, precisely regulating the trophoblast cell cycle progression. Knockout TMEM63B completely blocks these transport pathways, hinders the G1/S phase transition, inhibits proliferation, and ultimately induces defects in placental barrier construction and abnormal material transport functions, directly leading to perinatal embryonic death. This study establishes a novel regulatory paradigm for placental development involving mechanosensing coupled nucleoplasmic transport, providing clear new targets for early risk marker development and targeted intervention strategies for pregnancy complications.

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2. Wang Jing/Jiang Wenjian Collaborate to Reveal the Key ‘Switch’ of HFpEF Diastolic Dysfunction On

June 9, Wang Jing’s team from the Chinese Academy of Medical Sciences, together with Jiang Wenjian’s team from Capital Medical University, published a groundbreaking original report in the top cardiovascular journal Circulation, revealing for the first time the core regulatory ‘switch’ of heart failure (HFpEF) diastolic dysfunction with preserved ejection fraction. It provides a new intervention pathway for nearly 30 years of unresolved treatment bottlenecks in the global HFpEF field.
As a highly heterogeneous subtype accounting for over 50% of all heart failure cases, existing targeted HFpEF drugs can only reduce the risk of hospitalization and cannot reverse the core pathological phenotype of increased myocardial stiffness and decreased diastolic compliance, leaving significant unmet clinical needs. This study conducted high-resolution electron microscopy and transcriptome analysis of myocardial biopsy samples from 127 HFpEF patients of different etiologies, and for the first time identified the widespread presence of characteristic myofibrillary distortion in myocardium that had not been systematically reported, confirming that this phenotype is directly related to abnormal variable splicing of promyosin TPM1.
Mechanistic analysis clarified the complete pathogenic signal axis: kinase SRPK3 phosphorylates the splicing factor SRSF1, mediates abnormal skipping of exon 9a in TPM1, generating a large number of pathogenic TPM1b subtypes, directly disrupting the orderly assembly of muscle filaments, and ultimately inducing decreased myocardial elasticity and diastolic dysfunction.

The research team validated in multiple HFpEF animal models that myocardial targeted knockdown of SRPK3 or intervention using a self-developed highly selective inhibitor MSC1186 can completely reverse abnormal TPM1 splicing, restoring diastolic function to near normal levels in mice. The team has already initiated the MSC1186 preclinical IND application process and is expected to become the world’s first innovative HFpEF drug targeting variable splicing.

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3. ShanghaiTech University team Nature publishes: HuR molecular gel degraders may support colorectal cancer treatment

On June 10, Professor Cang Yong’s team from ShanghaiTech University published original research results online in the top international journal Nature, marking the world’s first report on targeted “non-druggable drugs” The specific molecular gel degrader dHuR for the RNA-binding protein HuR offers a breakthrough new therapeutic pathway for BRAF-mutant refractory colorectal cancer.
Clinical data show that about 10% of colorectal cancer patients carry BRAF functional acquisition activation mutations. The objective response rate of existing BRAF inhibitor monotherapy is less than 10%. Even with triple targeted therapy with BRAF + EGFR + MEK, the median progression-free survival is only 5.8 months. Nearly 70% of patients experience drug resistance progression within one year, and the long-term survival benefit falls far short of clinical expectations. As a core RNA-binding protein, HuR can bind to the 3′ UTR AU enrichment region of downstream oncogene mRNA, maintaining the stability of core onco-promoting transcripts such as BRAF, EGFR, and MEK. It is a key upstream regulator driving the malignant progression of BRAF-mutant colorectal cancer. However, previous position-occupied candidate drugs targeting HuR generally suffered from insufficient affinity and poor selectivity, and have never advanced to the clinical stage.

The newly developed dHuR efficiently mediates ubiquitin-modified modification and proteasome degradation by simultaneously binding CRBN ubiquitin ligase and HuR at the non-catalytic conserved interface, achieving over 85% tumor growth inhibition in a patient-derived xenograft tumor model with BRAF V600E mutation. Subsequent kinase-specific CRISPR screening further confirmed that combining EGFR or MEK inhibitors significantly enhanced dHuR cytotoxicity, completely avoiding the resistance mutation site limitations of existing BRAF inhibitors. The project has now entered the IND-enabled research phase, with clinical trial applications expected to be submitted in 2027, offering a novel treatment option for hundreds of thousands of patients with refractory BRAF-mutated colorectal cancer.

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4. Nature: Mu Yu and Wu Si collaborate to reveal the neural mechanisms

of the brain’s experiential decision-making On June 10, Mu Yu’s research group at the Chinese Academy of Sciences and Wu Si’s team from Peking University published a breakthrough achievement in cognitive neuroscience online in the top international journal Nature. Relying on the core single-cell resolution calcium imaging technology for zebrafish juveniles whole-brain, the system systematically reveals for the first time the general neural mechanisms by which the brain regulates subsequent decision-making behaviors based on past experience, filling a long-standing gap in core pathway research in this field.
Previously, academia has confirmed that in common scenarios of natural environmental gradient changes, sequence-dependent decision-making (i.e., adaptive behavior patterns adjusted based on recent experiences) is widespread across species, with neural correlations covering the entire central nervous axis. However, the complete transmission pathway for historical perception information to be stably maintained, dynamically updated in the brain, and ultimately transformed into subsequent choice biases has never been resolved, greatly restricting the development of intervention targets for cognitive decision-like neurological diseases.
This study uses whole-brain function map screening to accurately identify hierarchical functional circuits mediating experience retention and decision shifts: upstream dorsal thalamus discrete attractor neuron clusters stably encode historical perception information (such as obstacle spatial location), while downstream hindbrain dedicated integrator nuclei synchronously interface with thalamic input and current real-time sensory cues. The collaborative operation of these two modules directly determines the final behavioral output bias.

The brain-wide bionic computing model constructed in this study can fully reproduce all behavioral characteristics of empirically dependent decision-making, clarifying that the “attractor-integrator” dual-layer architecture is a general operating principle for historically biased decision-making. This not only provides core evidence for the evolutionary conservatism of empirical decision-making in higher animals, but also offers new core target directions for mechanistic analysis and new drug development for clinical conditions such as early decision-making decline in Alzheimer’s disease and rigid decision-making in autism.

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5. Huazhong University of Science and Technology Discovers Mitochondrial Switch

to Reverse T Cell Exhaustion On May 20, a joint team from Lan Peixiang and Xiong Hua from Huazhong University of Science and Technology announced an original breakthrough, identifying for the first time the core “braking protein” PARK7, which regulates T cell mitochondrial function, offering a novel druggable target for reversing T cell terminal exhaustion.
Currently, the clinical conversion rate of PD-1/PD-L1 inhibitors and autologous CAR-T therapies in the field of solid tumors has long been below 30%. The core limiting factor is that under long-term antigen stimulation in the tumor microenvironment, tumor-infiltrating CD8+ T cells undergo irreversible exhaustion, and the upstream regulatory pathways for mitochondrial dysfunction have long remained unclear. This team confirmed for the first time that the PARK7 protein, previously associated with neurodegenerative diseases, is abnormally highly enriched in exhausted T cell mitochondria mitochondria. As a non-classical deacetylating enzyme, it directly binds to the core mitochondrial membrane regulatory protein ATAD3A, removes acetylation modifications at key functional sites, blocks mitochondrial nuclear assembly and mtDNA transcription, significantly reduces the sustained capacity of oxidative phosphorylation, and ultimately drives T cells to exit their effector state and move toward terminal exhaustion.
In vivo functional experiments show that after T cell-specific knockout of PARK7, mitochondrial copy number increased by 217%, the proportion of the double positive depletion marker PD-1+TIM3+ decreased by 62%, the proportion of long-acting memory-like anti-tumor T cell subsets increased by 3.2 times, and combined with PD-1 inhibitors, the complete anti-tumor response rate in tumor-bearing mice increased from 28% to 79%. Industry experts believe the discovery of the PARK7-ATAD3A axis fills a target gap in mitochondrial regulation of T cell exhaustion. Related small molecule inhibitors have now entered the lead compound optimization stage and are expected to significantly improve the response rate to solid tumor immunotherapy in the future.

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6. The team discovers a new mechanism by which lncRNA-encoded micropeptide PAMPs inhibit proline metabolism in lung adenocarcinoma. Recently, Liu Pengyuan and Lu Yan’s team from Zhejiang University published a major original achievement in the field of lung adenocarcinoma metabolic intervention in the top international journal EMBO Molecular Medicine. For the first time, they identified a novel functional micropeptide PAMP encoded by long non-coding RNA (lncRNA) PSMA3-AS1, providing a new candidate intervention direction to address current industry challenges of targeted drug resistance and the lack of highly selective metabolic targets for lung adenocarcinoma.

Statistics show that lung adenocarcinoma accounts for more than 60% of all pathological types of lung cancer. Its driver gene-mediated proline metabolic reprogramming is the core pathway for tumor cells to resist oxidative stress and maintain rapid proliferation. However, current intervention molecules targeting the proline synthesis axis have long had shortcomings such as poor selectivity and high off-target toxicity. This study validated a large-sample clinical cohort and confirmed that PSMA3-AS1 and its encoding product PAMP are significantly and widely downregulated in lung adenocarcinoma tissues. Their expression levels are significantly positively correlated with progression-free survival and overall survival, with low expression groups increasing the risk of poor prognosis by 2.7 times.
Mechanistic studies have shown that PAMPs can directly bind to the catalytic domain of the key rate-limiting enzyme PYCR1 for proline synthesis through specific amino acid motifs, blocking its enzyme activity, reducing intracellular proline synthesis and accumulation, thereby effectively inhibiting lung adenocarcinoma cell proliferation and tumor formation in vivo. The study further identified two key amino acid sites where the two interact, providing precise modification targets for subsequent molecular optimization.

Notably, the in vitro synthetic PAMP can be efficiently internalized by lung adenocarcinoma cells without additional transmembrane modification, demonstrating excellent anticancer effects in both cell and animal models, with extremely high potential for peptide drug development, opening up a new track for precision treatment of lung adenocarcinoma.

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7. Shanghai Jiao Tong University team achieves dual-target therapy for autonomous dopamine

synthesis in the brain. On June 11, the core achievement of Parkinson’s disease (PD) gene therapy independently developed by Liu Jun’s team at Ruijin Hospital affiliated with Shanghai Jiao Tong University was officially published in Nature MedicineThis research completed Phase I clinical validation of China’s first self-developed AAV-type PD gene therapy, marking a key breakthrough in the in vivo curative treatment track for central nervous system degenerative diseases.
Currently, over 6 million PD patients worldwide rely long-term on levodopa drug interventions. After 5-10 years of treatment, complications such as motor fluctuations and refractory abnormalities commonly occur. Current symptomatic therapies cannot stop disease progression. Previously, overseas PD gene therapies have always been limited by the natural packaging upper limit of 4.7 kb for AAV vectors: three-target (TH/AADC/GCH1) strategies often suffer from insufficient packaging efficiency and uneven target expression, while single-target AADC supplement therapies cannot achieve endogenous dopamine synthesis. Both technologies have clear clinical shortcomings.
This study adopted a multicenter, open-label, dose-escalating design, including 10 patients with moderate to late PD with severe motor fluctuations. Through stereotactic surgery, the novel candidate therapy BBM-P002 was delivered to both calamen nuclei: The team modified tyrosine hydroxylase (TH) through constitutive activated mutations, enabling substrate catalysis without additional GTP cyclic hydrolase supplementation, and adapting to AAV packaging thresholds using only dual expression frames. Achieves efficient codelivery of TH and aromatic L-amino acid decarboxylase (AADC), supporting closed-loop autonomous synthesis of dopamine in situ in the brain.
12-month follow-up data showed that all therapies met the predetermined primary endpoint, with no dose-limiting toxicities or vector-related serious adverse events. Preliminary efficacy signals indicated that the duration of OFF-phase movement disturbance decreased by 47% compared to baseline, and UPDRS III motor scores improved significantly, fully validating the safety of the technical approach and providing core evidence-based evidence for subsequent phase II confirmatory clinical trials. Breaking the patent barriers of overseas generic therapies.

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8. Mol Cell: Antibodies Command TRIM21 Protein to Eliminate Invading Pathogens

from the Inside Recently, the UK Medical Research Council (MRC) Molecular Biology Laboratory team published a major original report in Molecular CellFor the first time, a complete closed-loop system confirmed the complete regulatory chain of a novel intracellular innate immune defense pathway called “antibody-guided heterophagy (ADX),” filling a long-standing research gap in the mechanisms of intracellular pathogen clearance and pointing new directions for the development of novel anti-infective drugs.

The research team cross-validated the findings by proximal linker tracing, CRISPR full gene editing knockout cell models, and live pathogen attack experiments, confirming that E3 ubiquitin ligase TRIM21 is an irreplaceable core hub of the ADX pathway: unlike traditional intracellular autophagy, which directly recognizes pathogen surface moleculesTRIM21 can specifically bind to the Fc region of the “antibody-pathogen” complex that invades the cytoplasm, rapidly catalyzes the modification of mixed K48/K63 polyubiquitin chains, recruits classic autophagy receptors such as p62 and NDP52, and delivers intact pathogen particles to the lysosomes for degradation, achieving cross-level linkage between humoral immunity and intracellular innate immunity.

In vivo functional validation showed that the ADX pathway exhibited broad-spectrum protective activity against more than ten intracellular bacteria and viruses, including Salmonella and adenovirus. After exposure, the organ load in wild-type mice was 2.7 orders of magnitude lower than in the TRIM21 knockout group, and the organ pathology injury score dropped by 68%. Currently, the academic community has clarified that ADX is a core intracellular defense model independent of known pathways. Future development of TRIM21 agonist anti-infective candidates targeting this target may help solve the current clinical challenges in treating multidrug-resistant intracellular infections.

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9. Zhou Haibo and his team discover new targets  for treating depression

On June 10, the neurofunctional genomics team led by Zhou Haibo published a breakthrough in the field of major depressive disorder (MDD) online in Nature GeneticsFor the first time, a brain-targeted adeno-associated virus (AAV)-mediated in vivo Perturb-seq high-throughput screening system was established, opening up a functional transformation pathway for long-term MDD genome-wide association studies (GWAS).

Previously, over 200 significant genome-wide risk loci for MDD have been reported worldwide, but over 90% are located in non-coding regulatory regions. Traditional in vitro cell models and low-throughput single-gene validation strategies cannot systematically elucidate their physiological and functional associations, resulting in long-term bottlenecks in monoamine target competition for new MDD drug development. In this study, the team conducted parallel functional deletion screening of 127 high-confidence MDD risk genes in adult mouse native brain neurons, simultaneously capturing whole-genome transcriptional disturbance effects at single-cell resolution. By cross-species matching of postmortem and peripheral transcriptome cohorts of thousands of MDD patients, they identified the core MDD risk functional gene cluster for the first time, confirming that functional loss of these genes generally induces significant downregulation of the neuronal oxytocin signaling pathway.

The study further used Dennd1a as a landmark target to validate its function in vivo: neuron-specific downregulation of Dennd1a can directly induce typical depressive-like behaviors such as anhedonia and social avoidance in mice, while the targeted enhancement of the oxytocin pathway not only reverses all depression-like phenotypes in mice but also restores normal signal transmission in prefrontal neurons differentiated by human iPSCs. This study provides a novel antidepressant target at the genetic evidence level. The team also mentioned that more precise perturbation strategies such as base editing will be used in the future to further eliminate analytical bias and accelerate the preclinical translation of candidate targets.

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10. Hepatology: Sun Yat-sen and Peking University team collaborate to analyze incomplete ablation of the spatial microenvironment

for hepatocellular carcinoma. In June 2026, the top international liver disease journal Hepatology published a report by Sun Yat-sen University Zhuang Bowen, Xie Xiaoyan’s team, together with Zeng Zexian’s team at Peking University, completed an original study that, for the first time, analyzed the microenvironmental evolution mechanism of incomplete thermal ablation hepatocellular carcinoma from the spatial multi-omics perspective, providing a new and precise intervention direction to address the long-standing clinical challenge of high post-ablation recurrence.

As the core curative method for early-stage hepatocellular carcinoma, radiofrequency ablation offers minimally invasive advantages and covers nearly 40% of patients with early-stage liver cancer under 3 cm. However, clinical data show that about 15% of patients experience incomplete ablation: the residual tumor induced by sublethal fever stimulation increases invasiveness, and the formation of an immunosuppressive microenvironment directly drives subsequent recurrence and metastasis. Previously, due to technical limitations, the academic community had not been able to clarify the underlying mechanism at the in situ spatial level.

This research team conducted high-precision spatial transcriptome sequencing on clinical cohort samples undergoing supplemental surgical resection after incomplete radiofrequency ablation. After integrating multicenter sequencing datasets, For the first time, a unique ‘heat stress invasion niche’ at the ablation boundary was identified, clarifying that the transcription factor CEBPD is the core regulatory switch for this niche: sublethal fever stimulation activates the transcriptional activity of CEBPD, initiating a paracrine cascade of the CXCL2-SPP1 signaling axis downstream, recruiting immunosuppressive tumor-associated macrophage infiltration, simultaneously inducing epithelial-mesenchymal transformation and CD8+ T cell exhaustion, ultimately driving therapeutic resistance and distant invasion.

In vivo functional validation shows that targeted blocking of this signal axis can inhibit residual tumor growth by up to 72% after ablation, while increasing PD-1 immunotherapy response rate by 2.8 times. This achievement fills a gap in the study of the spatial microenvironment for incomplete ablation of liver cancer, providing clear theoretical support and candidate targets for new strategies combining perioperative targeted and immunological ablation, and is expected to improve the existing full-process management system for liver cancer ablation.

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