Aloe emodin is an anthraquinone of traditional Chinese medicine monomer, which plays a protective action in cardiovascular diseases. However, the regulatory mechanisms of aloe emodin in the protection of radiation‐induced heart damage (RIHD) are unclear. As a novel post‐translational modification, lactylation is considered as a critical mediator in inflammatory cascade and cardiac injury. Here, using a cross of differential omics and 4D label‐free lactylation omics, protein disulfide‐isomerase (P4HB) is identified as a novel target for lactylation, and aloe emodin inhibits the binding of lactate to the K311 site of P4HB. Aloe emodin stabilizes kynurenine metabolism through inhibition of aspartate aminotransferase (GOT2) accumulation on damaged mitochondria. Mechanistically, aloe emodin inhibits phosphorylated glycogen synthase kinase 3B (p‐GSK3B) transcription in the nucleus to repress the interaction of prostaglandin G/H synthase 2 (PTGS2) with SH3 domain of SH3 domain‐containing GRB2‐like protein B1 (SH3GLB1), thereby disrupting the functions of mitochondrial complexes and reducing SH3GLB1‐mediated mitoROS accumulation, eventually suppressing calcium‐binding and coiled‐coil domain‐containing protein 2 (NDP52)‐induced mitophagy. This study unveils the regulatory role of aloe emodin in RIHD alleviation through PTGS2/SH3GLB1/NDP52 axis, indicates aloe emodin stabilizes GOT2‐mediated kynurenine metabolism through P4HB lactylation. Collectively, this study provides novel insights into the regulatory mechanisms underlying the protective role of aloe emodin in cardiac injury, and opens new avenues for therapeutic strategies of aloe emodin in preventing RIHD by regulating lactylation.

Lactate accumulation is a central feature of tumor metabolic reprogramming, yet its spatial and cell-type-specific effects in cancer, such as lung adenocarcinoma (LUAD), remain poorly defined. We integrated single-cell transcriptomics, spatial transcriptomics, spatial metabolomics, and immunofluorescence with TCGA survival data and machine-learning models. High-lactate tumors exhibited increased epithelial and fibroblast abundances, whereas T/NK cells and monocytes/macrophages were enriched in low-lactate samples. Spatial metabolomics revealed cell-type–restricted lactate and pyruvate distributions, with endothelial cells showing minimal lactate accumulation. Endothelial subclusters in high-lactate tissues displayed angiogenic and stress-response signatures and were strongly associated with poor prognosis. Multiple machine-learning frameworks—including random forest, elastic-net regression, SVM, ANN, and decision-tree models—consistently identified endothelial and fibroblast programs as key determinants of high-lactate states and adverse clinical outcomes. Collectively, our multi-omics spatial profiling demonstrates that lactate reshapes the LUAD microenvironment by driving angiogenesis, immune suppression, and prognostic stratification, highlighting lactate-centered pathways as promising therapeutic targets.

Ovarian cancer (OC) is a malignant neoplasm that displays increased vascularization. Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that functions as a regulator of cell metabolism and angiogenesis and plays a critical role in tumorigenesis. However, the precise role of ANGPTL4 in the OC microenvironment, particularly its involvement in angiogenesis, has not been fully elucidated. Our study demonstrates a significant upregulation of ANGPTL4 in OC specimens and its strong association with unfavorable prognosis. RNA-seq analysis affirms that ANGPTL4 facilitates OC development by driving janus kinase 2- signal transducer and activator of transcription 3 (JAK2-STAT3) signaling pathway activation. The interaction between ANGPTL4 and endothelial cell-specific molecule 1 (ESM1) promotes ANGPTL4 binding to lipoprotein lipase (LPL), thereby resulting in reprogrammed lipid metabolism and the promotion of OC cell proliferation, migration, and invasion. In the OC microenvironment, ESM1 may interfere with the binding of ANGPTL4 to integrin and vascular-endothelial cadherin (VE-Cad), which leads to stabilization of vascular integrity and ultimately promotes angiogenesis. Collectively, our findings underscore that ANGPTL4 promotes OC development via JAK signaling and induces angiogenesis in the tumor microenvironment through its interaction with ESM1.