• A precision medicine pipeline identifies ovarian cancer sensitivity to CRL4 inhibitors.

• CRL4 inhibition induces activation of mitogen-activated protein kinase signalling as identified by RNA sequencing, proteomics, and phosphoproteomics.

• Inhibitor combinations that target both CRL4 and this CRL4 inhibitor-induced survival signalling enhance ovarian cancer sensitivity to treatment.

NETs promote metastatic growth of LUAD by promoting YTHDF2-mediated SLC2A3 mRNA degradation, inhibiting ferroptosis and CD8(+) T cell activity.

Excessive muscular fatty infiltration in post-menopausal women arose from the disruption of the methyltransferase-like 3 (METTL3)–oestrogen receptor 1 (ESR1)-mediated loop of fibro/adipogenic progenitors (FAPs) due to oestrogen deficiency. Reactivation of the METTL3–ESR1-mediated loop by oestrogen alleviated excessive adipogenesis in FAPs, thereby ameliorating muscular fatty infiltration and improving locomotor function in ovariectomy (OVX) mice.

This study demonstrated how KMT2A–WDR5 regulate pro-fibrotic factor PU.1 through catalysing H3K4me3 at the promoter. We suggested both knocking down KMT2A and inhibiting KMT2A transcription complex could attenuate lung fibrosis, which indicating new therapeutic strategy for clinical practice.

• NKAα1 downregulation impairs endothelial function in diabetes by promoting oxidative/nitrative stress and ferroptosis.

• NKAα1 supports lysosomal degradation of ACSL4 via autophagy, preventing lipid peroxidation and ferroptosis.

• Hamaudol, an activator of NKAα1, restores endothelial relaxation in diabetic mice by inhibiting NKAα1 phosphorylation and endocytosis.

• Peripheral immune suppression and pulmonary immune hyperactivation characterise the distinct immune landscapes in anti-MDA5+DM with RP-ILD.

• Circulating monocytes transition from an immunosuppressive phenotype in the periphery to proinflammatory and profibrotic Mo-AMs in the lungs.

• Chemokines produced by Mo-AMs drive monocyte and other immune cell recruitment to the lungs, amplifying pulmonary inflammation.

Lung cancer-related changes in fragmentomic features were unevenly distributed across the genome, showing significant enrichment in epigenetically regulated regions of specific genes.

The cfDNA fragmentomics-based model demonstrated superior detection capability, especially for early-stage lung cancer.

This study offers novel insights into cfDNA biology and paves new avenues for the accurate and cost-effective early detection of lung cancer.

An overview of the paclitaxel resistance mechanism induced by RNF31-mediated ALYREF subcellular distribution. RNF31 promoted the linear ubiquitination of ALYREF, subsequently enhancing ALYREF nuclear transport via IPO13 upon PTX treatment. In addition, RNF31-mediated ubiquitination of ALYREF facilitated ALYREF binding and export of PTX resistance-related factors, including TUBB3, STMN1, and TAU, ultimately leading to PTX resistance in TNBC. Thiolutin, an inhibitor of RNF31, enhanced PTX sensitivity in TNBC.

HSPG2 level in BM EPCs of AML-CR patients was decreased, which was related to the reduced BM EPC function. HSPG2 knockdown or Ara-C intervention reduced HSPG2 level and led to BM EPC dysfunction, HSPG2 treatment could repair these damages and restored the BM EPC function of AML-CR patients.

DNA-PKcs knockdown heightens osteosarcoma sensitivity to anlotinib.

DNA-PKcs modulates anlotinib-induced protective autophagy through interacts with Beclin-1 and regulates its ubiquitination.

m⁶A modification of OLE_LINK82PRKDC mRNA induced by METTL3 contributes to anlotinib resistance in osteosarcoma.

m⁶A methylation of PRKDC mRNA recognised by YTHDF1 amplifies the expression of DNA-PKcs.

Chaperone-mediated autophagy (CMA) deficiency in hepatocytes promotes hepatic inflammation and fibrosis in mice with nonalcoholic steatohepatitis (NASH) by inducing cholesterol accumulation and endoplasmic reticulum (ER) stress.

Upregulated FOXM1 impairs CMA by suppressing the transcription of lysosome-associated membrane protein 2A (LAMP2A), a rate-limiting component of CMA.

ER stress increases FOXM1 expression and cholesterol accumulation.

FOXM1/CMA/ER stress axis forms a vicious circle and promotes the development of NASH.

Solid tumours are complex ecosystems characterised by significant heterogeneity in both their component composition and spatial‒temporal organisation. This complexity contributes to challenges in accurate stratification, as well as in the development of drug resistance and early relapse. Our study maps the transcriptional architecture of human liver cancer using high-resolution Stereo-seq and single-cell RNA sequencing across various tissue types, and we identified a 500 µm-wide zone centred around the tumour border in patients with liver cancer, referred to as ‘invasive zone’. We detected strong immunosuppression, metabolic reprogramming and severely damaged hepatocytes in this zone. Similarly, the invasive zone between tumour tissues and paratumoural tissues of solid tumours resembled the border area of the two opposing powers, namely, ‘Chu’ and ‘Han’ Dynasties in fighting for hegemony in the late Qin Dynasty. The most intense heavy fighting and complex mutual interactions were found around the battlefronts of the two powers, which was called ‘Honggou’, namely, the wide chasm in the history like ‘invasive zone’. Furthermore, when the smoke of war gradually dissipated in the long river of history, the border area between Chu and Han Dynasties was forever fixed on the Chinese chess board and represented the balance between offense and defense.

Performed comprehensive genomics across liver biopsies of 396 MASLD patients and identified patients with increased, decreased and unchanged FGF21 expression.

Used genomic data from FGF21 transgenic, knock-out and animal MASLD models treated with synthetic FGF21 analogues to identify FGF21-mode-of-action and metabolic networks in human MASLD.

Given the significant heterogeneity in FGF21 expression, not all patients will benefit from FGF21-based therapies.

1. Distinct immunotypes are identified in the CRC macroenvironment.
2. TLS and immunotherapy exert influence on the immune macroenvironment.
3. TLS presence correlates with patient survival, CMS and therapeutic efficacy of ICI.
4. PD-1 and CD69 expressed in CD8+ Tem from blood can predict TLS presence in the CRC macroenvironment.

• ZFP14 under-expression is associated with ccRCC tumourigenesis and progression.

• METTL14-mediated m6A enhances ZFP14 mRNA stability and expression with IGF2BP2 as the reader in ccRCC.

• ZFP14 promotes the degradation of STAT3 by enhancing its K48-linked ubiquitination, inhibiting ccRCC progression.

1. 5hmC epigenetic markers derived from portal venous blood could accurately predict metachronous metastasis of colorectal cancer.
2. PDE4D was a key metastasis-driven target that promoted metachronous metastasis via the HIF-1α-CCN2 pathway.
3. The newly synthesised compound L11 could specifically inhibit PDE4D and abolish metachronous metastasis of colorectal cancer without obvious toxic side effects.

• In vivo application of a therapeutic gene editing strategy for permanent deletion of the pathogenetic CTG-repeat amplification in the DMPK gene that causes myotonic dystrophy type 1.
• Following treatment, diseased mice show a significant improvement of both molecular and phenotypic defects.

1. E2F1-mediated CDK5 activation drives mitochondrial dysfunction in microglia, exacerbating CIRI damage.
2. Mitochondrial fission and impaired mitophagy are key processes influenced by E2F1-CDK5 signalling in CIRI.
3. Targeting the E2F1-CDK5-DRP1 axis offers novel therapeutic strategies for mitigating CIRI-induced brain injury.

• Single-cell RNA (ScRNA) atlas across types of endometriosis is established.
• Mesothelial cells are founded in ovarian endometriosis.
• Endometriosis-associated mesothelial cells (EAMCs) experience various level of epithelial–mesenchymal transition (EMT) process in different subtypes.
• EAMCs may exert an influence on progesterone resistance in stromal cells through intercellular communication mediated by the FN1-AKT pathway.

1. Seipin^−/− mice, which lack adipose tissue, exhibit significantly impaired TRAS and delayed liver regeneration following partial hepatectomy.
2. Transplantation of normal adipose tissue into Seipin^−/− mice restores TRAS and enhances liver regeneration, highlighting the essential role of adipose tissue in these processes.
3. Liver-specific overexpression of Seipin has no effect on TRAS and liver regeneration in Seipin^−/− mice.

The biological function of METTL1 in cancer. METTL1 regulates the processes involved in the development of cancer, including tumour proliferation, migration, invasion, angiogenesis, chemotherapy and radiotherapy resistance, energy metabolism and TIME suppression.

1. SHP2 plays a pivotal role as a signal transducer in the MAPK/ERK signaling pathway.
2. SHP2 controls the cell cycle via the GSK3β/cyclin D1/Rb pathway in oncogenic KIT-driven GIST.
3. Inhibition of SHP2 synergizes with adjuvant therapy drugs in inhibiting KIT-driven GIST with primary and secondary mutations both in vitro and in vivo.