In this issue, eight major achievements of national medicine were selected, and eight core scientific research breakthroughs were disassembled, including neuroblastoma, KRAS mutant solid tumor, fundus AI chronic disease screening, nuclear glycosylation function, bacterial immune activation, hereditary enteritis, sf3b1 mutant tumor, and diabetic heart disease. They focused on target cracking of difficult patent drugs, noninvasive early screening technology, new mechanisms of gene regulation, and new targets of disease targeting, providing cutting-edge references and academic insights for basic research and clinical transformation of biomedicine, and research and development of innovative drugs.
Biology, medicine, science and technology

1、 Zhejiang University team reveals a new mechanism of neuroblastoma malignancy

Neuroblastoma (NB) is the extracranial malignant solid tumor with the highest mortality rate in children. MYCN amplification exists in nearly 50% of high-risk cases. The 5-year survival rate of patients with this subtype is less than 30%. The existing treatment options are easy to be resistant. Because N-myc belongs to the typical “non druggable” transcription factor, direct targeting strategy is difficult to break through for a long time, and there is an unmet urgent need in clinic.

On April 29, the team of Ying meidan, heqiaojun and shaoxuejing of Zhejiang University published a breakthrough study in the international top journal Molecular Cell, which systematically clarified the key regulatory role of S-acylation post-translational modification on N-myc transcriptional activity for the first time, and identified palmitoyltransferase zdhhc22 as the core driving node of this oncogenic pathway. The mechanism study showed that zdhhc22 specifically catalyzed the S-acylation modification of N-myc and significantly enhanced its oncogenic transcriptional activity; .

The team verified by in vitro NB cell line, in vivo xenograft tumor and patient derived organoid model that targeted inhibition of zdhhc22 can effectively block the oncogenic activity of N-myc, significantly inhibit the proliferation of MYCN amplified neuroblastoma, and restore the sensitivity of tumor to chemotherapy. This study broke through the existing bottleneck of N-myc targeting research, and identified zdhhc22 as a potential druggable target for high-risk n-myc-driven neuroblastoma, laying a core theoretical foundation for subsequent targeted inhibitor development and clinical transformation.

2、 New drug setidegrasib brings early hope for lung and pancreatic cancer

KRAS is the most classic “refractory” oncogenic target in the field of solid tumors, of which G12D is the subtype with the highest proportion of KRAS mutations: about 30% of advanced non-small cell lung cancer and more than 40% of pancreatic cancer have KRAS G12D mutations. There has been no approved specific targeted therapy in the world before. The prognosis of the two types of patients is extremely poor, and the clinical demand gap is huge. Recently, the New England Journal of Medicine (NEJM) published the phase I clinical results of setidegrasib, a targeted drug under development, bringing hope for early treatment of such refractory patients.

Setidegrasib belongs to the protein degradation targeting chimera (protac) analog, which is different from the space occupying inhibition mechanism of traditional targeted drugs: the drug can simultaneously bind KRAS G12D protein and intracellular E3 ubiquitin ligase, deliver KRAS G12D to the proteasome system through ubiquitin labeling to complete degradation, and block oncogenic signals from the root. This international multicenter phase I trial included 203 patients with advanced stage of treatment in 28 centers in 5 countries, and ultimately determined 600mg intravenous injection once a week as the recommended dose for subsequent clinical use.

According to the industry view, targeting KRAS mutations by protein degradation strategy has the advantage of mechanism level, but there is still potential risk of off target degradation of degradation agents. This is a proof of concept early result, and confirmatory tests will be carried out to verify the clinical benefit. If approved successfully, it will rewrite the treatment pattern of KRAS G12D mutant solid tumors.

3、 Take a picture of your eyes. Chronic diseases are known early: “pupil reading” Ai screens six systemic diseases in 30 seconds

Recently, the AI chronic disease screening results developed by yuhonghua’s team were officially published in the international top medical journal Nature · medicine. The multi task deep learning retinal imaging framework reti pioneer developed by the team realized the non-invasive and rapid screening of multiple systemic diseases based on ordinary fundus photography, opening up a new technological path for the early screening of affordable chronic diseases.

At present, the screening of high incidence systemic chronic diseases such as type 2 diabetes and gout generally has pain points such as cumbersome process, strong invasiveness and insufficient grass-roots coverage. The academic community has long confirmed that retinal vascular and microstructure characteristics can reflect systemic metabolic damage, but there has always been a lack of stable and generalizable multi disease joint detection AI scheme. The study completed the model training and development based on 107730 standardized color fundus photographs, which can complete the synchronous screening of six target systemic diseases at one time; Internal validation showed that the model achieved excellent performance in terms of the area under the receiver operating characteristic curve (AUC) for various diseases, and the excellent generalization ability was verified in six independent external cohorts across devices and populations. At the same time, it had clear biological interpretability, and solved the common “black box” problem of AI medical applications.

The real-world primary care hidden trial showed that the average time of single case screening of this model was only 30.6 seconds, and the efficiency was much higher than the traditional standard laboratory screening process; . This study bridged the technical gap of the current inclusive chronic disease screening, provided the core support for the whole-body health assessment driven by ophthalmology, and had a high value of grassroots implementation and transformation.

4、 Sun Yat sen University and other teams found that the N-glycan Guardian genome “forbidden zone” was stable

N-linked glycosylation is one of the post-translational modifications of core proteins in eukaryotes. According to classical cognition, this modification only acts on the secretory and membrane proteins of the endoplasmic reticulum and Golgi pathway, and its distribution and function in the nucleus have not been revealed for a long time. On April 28, 2026, the team led by dingjunjun of Sun Yat sen University published breakthrough research in nature cell biology, a top Cell Biology journal, which systematically analyzed the new function of N-glycosylation modification of inner nuclear membrane proteins to maintain genome stability for the first time.

This study confirmed that the endoplasmic reticulum canonical N-glycan biosynthesis pathway can mediate the N-linked glycosylation of inner nuclear membrane proteins. This kind of nuclear N-glycans are specifically enriched in the nuclear lamina associated domain (LAD) – that is, the “forbidden zone” in the genome to maintain transcriptional silencing and structural compression, and is the core functional region to ensure the stability of genome structure. The study clarified the regulatory mechanism: N-glycosylation can mediate the interaction between histone H3K9 methyltransferase setdb1 and inner nuclear membrane proteins, and stabilize the localization of setdb1 in the lad region; Inhibition of N-glycosylation or mutation of glycosylation sites of inner nuclear membrane proteins will lead to down-regulation of the inhibitory histone marker h3k9me3 in the lad region, causing loose heterochromatin and genome instability.

5、 Xiapengyan and other teams of Peking University found that CTH enzyme shears bacterial lipoproteins to activate immune alarm

Recognition of cytoplasmic pathogen associated molecular patterns by innate immunity is the core link of host defense against intracellular bacterial infection. As the key functional module of this process, non canonical inflammasome has long been a key cognitive gap in the upstream activation mechanism. On April 30, xiapengyan team of Peking University and Wang Shuo team of Institute of Microbiology, Chinese Academy of Sciences published the latest research in Nature Immunology, an international top immunology journal, revealing for the first time the molecular mechanism of cytosolic cystathionine gamma lyase (CTH) as a non canonical inflammasome activated by bacterial lipoprotein receptor, filling the research gap in this field.

This study confirmed that CTH, a key metabolic enzyme of the methionine pathway in the cytoplasm of macrophages, has a non canonical immune receptor function: it can specifically recognize bacterial lipoproteins released by invading pathogenic bacteria, shear lipoproteins through its own enzymatic activity to generate lipid chains with free sulfhydryl groups, and the product is assembled through disulfide bonds to form an active molecule containing four acylated chains, which directly induces cleavage oligomerization of caspase-11 and completes the activation of non canonical inflammasomes. The study further clarified that the redox environment in macrophages can directly affect the activation process by regulating the efficiency of sulfhydryl assembly; Functional validation in vitro and in vivo showed that CTH deficient macrophages completely lost the immune response ability to cytoplasmic bacterial lipoproteins, and the inflammatory response and bacterial clearance ability of CTH deficient mice to intracellular bacterial infection were significantly attenuated.

This study solved the long-term mystery of non canonical inflammasome activation pathway, revealed the regulatory association between cellular redox homeostasis and anti infection immunity, and provided a new intervention target for inflammation related diseases such as bacterial sepsis.

6、Zhejiang University team reveals the mechanism by which TLR1 gene defects trigger enteritis

On April 28, the zhouqing team of Zhejiang University published the latest immunological research in the proceedings of the National Academy of Sciences (PNAs), which systematically elucidated the molecular mechanism of immune dysregulated colitis caused by loss of function variants of Toll like receptor 1 (tlr1) for the first time, providing a new direction for genetic diagnosis and targeted intervention of inflammatory bowel disease (IBD).

At present, the global incidence of IBD continues to rise. More and more studies have confirmed that the functional defects of innate immune molecules are the core genetic etiology of early-onset IBD, but the functional mechanism of most rare pathogenic variants has not yet been clarified. As a key pattern recognition receptor in innate immunity, tlr1 mainly recognizes pathogen related molecular patterns by forming heterodimers with TLR2. Previous studies have only suggested that tlr1 dysfunction is associated with immune disorders, and its specific role in regulating intestinal immune homeostasis is not clear.

This study identified a novel homozygous truncating tlr1 pathogenic variant from a cohort of patients with early-onset immune dysregulated colitis. Functional validation revealed that although the patient’s peripheral blood mononuclear cells presented a clinically relevant strong inflammatory phenotype, they had congenital tlr1 signaling response defects; After stimulated by ligands, there were significant obstacles in the production of bactericidal effector molecules and anti-inflammatory factor IL-10 of tlr1 deficient cells, which eventually led to the impairment of pathogen clearance ability, the failure of normal termination of inflammatory response, and the breaking of intestinal immune homeostasis.

Animal experiments further confirmed that the susceptibility of tlr1 knockout mice to intestinal infection and experimental colitis was significantly increased, and exogenous IL-10 supplementation could effectively improve the inflammatory phenotype. .

7、 Shanghai Jiao Tong University team found that sf3b1 mutation could precisely unlock specific tumors

Mutations in core components of the spliceosome are one of the key drivers of human tumorigenesis. The splicing factor sf3b1 is the gene with the highest mutation frequency among all splicing related oncogenes. Its hotspot mutations have long been observed to be highly tumor lineage specific: sf3b1 r625 mutations are mostly found in cutaneous melanoma, while k700e hotspot mutations are mainly enriched in hematological malignancies such as myelodysplastic syndrome, but the molecular mechanism of this mutation lineage preference has not been clearly explained, which seriously hinders the development of precision drugs for sf3b1 mutant tumors.

The latest research published by Zeng Hanlin’s team at Shanghai Jiao Tong University in science advances has solved this scientific mystery. Through systematic transcriptome splicing analysis, this study found that sf3b1 r625h mutation could induce stronger activation effect of alternative 3’splice site than k700e; Further molecular mechanism analysis confirmed that the sf3b1 r625h mutation has a natural binding preference for the polyadenine rich sequence around the cryptic branch point, and this abnormal splicing selectivity directly leads to preferential missplicing inactivation of NF1, a negative regulator of Ras signaling, which eventually triggers persistent overactivation of Ras pathway and accelerates melanoma progression.

This study redefined the lineage specific oncogenic paradigm of sf3b1 mutations, established Ras pathway activation as the core mechanism of sf3b1 r625h driving melanoma for the first time, provided a clear target for the precise targeted treatment of this subtype of melanoma, and also provided a key theoretical basis for the stratified diagnosis of different sf3b1 mutant tumors.

8、 Shandong University found that fibroblasts released CCN1 aggravated diabetic heart disease

Recently, the teams of Zhong Ming and Wang Zhihao of Shandong University published the latest research results in autophagy, an international authoritative journal in the field of autophagy, revealing the molecular mechanism of cardiac fibroblasts aggravating DCM by paracrine CCN1, and clarifying that CCN1 can be used as a potential target for DCM treatment. This study confirmed in the DCM mouse model and insulin resistant cell model that the expression of CCN1 (cysteine rich protein 61) was significantly increased in the diseased heart, and it was mainly derived from activated cardiac fibroblasts, which could significantly inhibit the autophagy activity of cardiomyocytes through paracrine effect. In vivo functional validation showed that fibroblast specific CCN1 gene knockout could effectively improve cardiac dysfunction, restore myocardial autophagy activity, and alleviate the progression of pathological myocardial fibrosis in DCM mice.

Further molecular mechanism analysis showed that CCN1 specifically bound to integrin α V β 1 (itgav-itgb1) on the surface of cardiomyocyte membrane through its cysteine knot domain, activated the downstream ptk2/fak-mtor signaling pathway to inhibit autophagy, and finally promoted the occurrence and development of DCM. This study improved the DCM pathogenesis network from a new perspective of cell-cell communication, and provided a clear molecular basis for the subsequent development of DCM targeted intervention drugs.

About Us

MeritsIP: Your Global Intellectual Property Partner

At MeritsIP, we provide comprehensive IP services in biomedicine, medical devices, manufacturing, semiconductors, and AI. We support 200+ top clients globally with strategic, high-quality IP services.

Stay Connected

• • Website: https://www.meritsipglobal.com

• • LinkedIn: Follow us on LinkedIn

• • Email: meritsip@meritsandtree.com

© 2025 MeritsIP. All Rights Reserved.