•Distinct immunotypes are identified in the CRC macroenvironment.

•TLS and immunotherapy exert influence on the immune macroenvironment.

•TLS presence correlates with patient survival, CMS and therapeutic efficacy of ICI.

•PD-1 and CD69 expressed in CD8+ Tem from blood can predict TLS presence in the CRC macroenvironment.

•5hmC epigenetic markers derived from portal venous blood could accurately predict metachronous metastasis of colorectal cancer.

•PDE4D was a key metastasis-driven target that promoted metachronous metastasis via the HIF-1α-CCN2 pathway.

•The newly synthesised compound L11 could specifically inhibit PDE4D and abolish metachronous metastasis of colorectal cancer without obvious toxic side effects.

•Identification of the E2F1/CDK5/DRP1 Axis in CIRI This study reveals that the E2F1 transcription factor upregulates CDK5 expression, which in turn phosphorylates DRP1, promoting excessive mitochondrial fission and inhibiting mitophagy in microglia. This mechanism plays a critical role in cerebral ischemia-reperfusion injury (CIRI).

•Mitochondrial Dysfunction and Neuroinflammation The activation of DRP1 leads to mitochondrial fragmentation and excessive ROS accumulation, triggering microglial activation and inflammatory responses, exacerbating neuronal apoptosis and brain injury in CIRI.

•Therapeutic Potential of E2F1 Silencing Knockdown of E2F1 in microglia effectively reduces mitochondrial damage, restores mitophagy, suppresses inflammation, and improves neurological outcomes in a CIRI mouse model, highlighting a promising therapeutic target for ischemic stroke intervention.

•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.

•RNF31 facilitated ALYREF-mediated PTX resistance in TNBC.

•RNF31 promoted ALYREF nuclear transport via IPO13 in response to PTX treatment, subsequently enhancing the export of mRNAs encoding PTX resistance-related factors, including TUBB3, STMN1, and TAU.

•Blocking RNF31 trapped ALYREF in the cytoplasm and induced TNBC cell death upon PTX treatment.

•Inhibiting RNF31 activity re-sensitized PTX-resistant TNBC to PTX treatment.

•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.

•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.

•The HSPG2 level in the BM EPCs of AML-CR patients was decreased, which was related to the reduced BM EPC function.

•HSPG2 knockdown or Ara-C intervention reduced the HSPG2 level and led to BM EPC dysfunction, which could be restored by HSPG2 treatment in vitro.

•HSPG2 treatment restored the BM EPC function of AML-CR patients without affecting their leukaemia cell-supporting ability.

•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.

•Our study elucidated the regulatory relationships between epigenetic modifications and their effects on fragmentomic features.

•Identifying epigenetically regulated genes provided a critical foundation for developing the cfDNA fragmentomics-based machine learning model.

•The model demonstrated exceptional clinical performance, highlighting its substantial potential for translational application in clinical practice.

•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.

•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.

•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.

•SHP2 plays a pivotal role as a signal transducer in the MAPK/ERK signaling pathway.

•SHP2 controls the cell cycle via the GSK3β/cyclin D1/Rb pathway in oncogenic KIT-driven GIST.

•Inhibition of SHP2 synergizes with adjuvant therapy drugs in inhibiting KIT-driven GIST with primary and secondary mutations both in vitro and in vivo.

•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.

•Seipin^-/- mice, which lack adipose tissue, exhibit significantly impaired TRAS and delayed liver regeneration following partial hepatectomy.

•Transplantation of normal adipose tissue into Seipin^-/- mice restores TRAS and enhances liver regeneration, highlighting the essential role of adipose tissue in these processes.

•Liver-specific overexpression of Seipin has no effect on TRAS and liver regeneration in Seipin^-/- mice.

•METTL1-mediated m7G modification is crucial for various biological processes, including RNA stability, maturation and translation.

•METTL1 has emerged as a critical epigenetic modulator in human illnesses, with its dysregulated expression correlating with multiple diseases progression and presenting opportunities for both diagnostic biomarker development and molecular-targeted therapy.

•Enormous knowledge gaps persist regarding context-dependent regulatory networks of METTL1 and dynamic m7G modification patterns, necessitating mechanistic interrogation to bridge basic research with clinical translation in precision medicine.

•The deubiquitinating enzyme USP25 was down-regulated both in myocardial ischemia/reperfusion injury (MI/RI) myocardium tissues.

•The deficiency of USP25 worsened exacerbated MI/RI in mice, whereas the overexpression of USP25 in cardiomyocytes mitigated this pathological phenotype.

•USP25 directly interacts with the NLRP3 protein and deubiquitinates it via K63 linkage at residue K243 through its active site C178, thus affecting NLRP3-ASC interaction and ASC oligomerization to inhibit NLRP3 activation and pyroptosis in cardiomyocytes.